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

A Randomized Phase 2/3 Multi-Center Study of SM-88 in Subjects With Pancreatic Cancer Whose Disease Has Progressed or Recurred

A prospective, open-label phase 2/3 trial in metastatic pancreatic cancer subjects who have failed two lines of prior systemic therapy. The trial is designed to evaluate the safety and efficacy of SM-88 used with MPS (methoxsalen, phenytoin and sirolimus) in pancreatic cancer and will measure multiple endpoints, including overall survival, progression free survival, relevant biomarkers, quality of life, safety, and overall response rate.

(Part 1 enrollment complete) In the initial stage of the trial (36 subjects), two dose levels of SM-88's metyrosine-derivative was evaluated.

(Part 2 actively enrolling) The second part will consist of a subsequent expansion of the trial to further assess safety and efficacy of SM-88 used with MPS containing the selected SM-88 RP2D from Part 1. A total of 250 subjects in the second part will be randomized 1:1 either to the SM-88 arm (125 subjects) or Physician's Choice of therapy for the Control Arm (125 subjects). Subjects should have previously received two lines of prior systemic therapy.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: SM-88 used with MPS (methoxsalen, phenytoin, sirolimus); Drug: Capecitabine, Gemcitabine, and 5-FU

Detailed Description

Please refer to Inclusion/Exclusion Criteria and Summary

• Study Type: Interventional
• Enrollment (Actual): 132
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama At Birmingham
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Santa Monica, California, United States, 90403
      • Sarcoma Oncology Research Center
  • Connecticut
    • New Britain, Connecticut, United States, 06053
      • Hartford Healthcare Cancer
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
    • Tampa, Florida, United States, 33613
      • Advent Health Florida Hospital Tampa
  • Iowa
    • Sioux City, Iowa, United States, 51101
      • June E. Nylen Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • University Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • Bronx, New York, United States, 10469
      • New York Cancer and Blood Specialist
    • East Setauket, New York, United States, 11733
      • North Shore Hematology Oncology
    • East Setauket, New York, United States, 11733
      • NY Cancer and Blood Specialist
    • New York, New York, United States, 10016
      • NYU Langone Health
    • New York, New York, United States, 10065
      • Weill Cornell
    • New York, New York, United States, 10028
      • Central Park Hematology & Oncology
  • Ohio
    • Columbus, Ohio, United States, 43221
      • The Ohio State University
  • Texas
    • Dallas, Texas, United States, 75246
      • Texas Oncology-Baylor
    • Houston, Texas, United States, 77030
      • MD Anderson
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 and Part 2 SM-88 Arm; (Part 1 enrollment complete) SM-88 used with MPS (methoxsalen, phenytoin and sirolimus) (Part 2 actively enrolling) SM-88 (920 mg per day) used with MPS (methoxsalen, phenytoin and sirolimus) will be administered to 125 evaluable subjects until unacceptable toxicity, disease progression, or any of the treatment discontinuation criteria are met.	Drug: SM-88 used with MPS (methoxsalen, phenytoin, sirolimus); Daily oral therapy for cancer; Other Names: SM-88; Racemetyrosine
Experimental: Physician's Choice; Physician's Choice therapy will be administered for a total of 125 evaluable subjects until unacceptable toxicity, disease progression, or any of the treatment discontinuation criteria are met.	Drug: Capecitabine, Gemcitabine, and 5-FU; Investigator choice of the following therapies: Capecitabine, Gemcitabine, and 5-FU; Other Names: Physician's Choice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	To determine the OS of subjects treated with SM-88 used with methoxsalen, phenytoin, and sirolimus (MPS) vs the Control Arm (Physician's Choice).	From date of randomization until the date of first documented progression or date of death, whichever came first, assessed up to 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	To report investigator determined PFS.	From date of randomization until the date of first documented progression or date of death, whichever came first, assessed up to 60 months

Collaborators and Investigators

• Sponsor: Tyme, Inc
• Investigators: Study Director: Giuseppe DelPriore, MD, MPH, Tyme, Inc

Publications and helpful links

General Publications

• Noel MS, Kim S, Hartley ML, Wong S, Picozzi VJ, Staszewski H, Kim DW, Van Tornout JM, Philip PA, Chung V, Ocean AJ, Wang-Gillam A. A randomized phase II study of SM-88 plus methoxsalen, phenytoin, and sirolimus in patients with metastatic pancreatic cancer treated in the second line and beyond. Cancer Med. 2022 May 2. doi: 10.1002/cam4.4768. [Epub ahead of print]

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2018
• Primary Completion (Actual): April 19, 2022
• Study Completion (Actual): April 19, 2022

Study Registration Dates

• First Submitted: April 18, 2018
• First Submitted That Met QC Criteria: April 27, 2018
• First Posted (Actual): May 1, 2018

Study Record Updates

• Last Update Posted (Actual): June 30, 2022
• Last Update Submitted That Met QC Criteria: June 28, 2022
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: chemotherapy; MPS; cancer; Pancreas; metastatic; Pancreatic cancer; Sirolimus; Pancreas cancer; Pancreatic; Phenytoin; 3rd line; low toxicity; SM-88; SM88; third line; CMBT; well tolerated; Racemetyrosine; Methoxsalen
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Photosensitizing Agents; Dermatologic Agents; Anti-Bacterial Agents; Membrane Transport Modulators; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Antibiotics, Antineoplastic; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Gemcitabine; Capecitabine; Sirolimus; Methoxsalen; Phenytoin
• Other Study ID Numbers: Tyme-88-Panc

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No