Clinical Trials /

A Multi-Center Study of SM-88 in Subjects With Pancreatic Cancer

NCT03512756

Description:

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.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: Tyme-88-Panc
  • NCT ID: NCT03512756

Conditions

  • Pancreatic Cancer

Interventions

DrugSynonymsArms
SM-88 used with MPS (methoxsalen, phenytoin, sirolimus)SM-88, RacemetyrosinePart 1 and Part 2 SM-88 Arm
Capecitabine, Gemcitabine, and 5-FUPhysician's ChoicePhysician's Choice

Purpose

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.

Detailed Description

      Please refer to Inclusion/Exclusion Criteria and Summary
    

Trial Arms

NameTypeDescriptionInterventions
Part 1 and Part 2 SM-88 ArmExperimental(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.
  • SM-88 used with MPS (methoxsalen, phenytoin, sirolimus)
Physician's ChoiceExperimentalPhysician'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.
  • Capecitabine, Gemcitabine, and 5-FU

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

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

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tyme, Inc

Trial Keywords

  • Pancreatic cancer
  • Pancreas cancer
  • Pancreatic
  • Pancreas
  • cancer
  • low toxicity
  • chemotherapy
  • metastatic
  • SM-88
  • SM88
  • 3rd line
  • third line
  • CMBT
  • well tolerated
  • MPS
  • Racemetyrosine
  • Methoxsalen
  • Sirolimus
  • Phenytoin

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