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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03512756
Recruitment Status : Recruiting
First Posted : May 1, 2018
Last Update Posted : September 19, 2019
Sponsor:
Information provided by (Responsible Party):
Tyme, Inc

Brief Summary:

A prospective, open-label phase 2/3 trial in metastatic pancreatic cancer subjects who have failed at least two lines of any 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.


Condition or disease Intervention/treatment Phase
Pancreatic Cancer Drug: SM-88 used with MPS (methoxsalen, phenytoin, sirolimus) Drug: Capecitabine, Gemcitabine, and 5-FU Phase 2 Phase 3

Detailed Description:
Please refer to Inclusion/Exclusion Criteria and Summary

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase 2/3 Multi-Center Study of SM-88 in Subjects With Pancreatic Cancer Whose Disease Has Progressed or Recurred
Actual Study Start Date : March 27, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


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 Name: Physician's Choice




Primary Outcome Measures :
  1. 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 ]
    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 :
  1. 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 ]
    To report investigator determined PFS.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03512756


Contacts
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Contact: Maria Loushin 212-461-2198 Maria.Loushin@TymeInc.com
Contact: Shabnam Stanicky 212-461-2196 Shabnam.Stanicky@TymeInc.com

Locations
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United States, Alabama
University of Alabama at Birmingham Not yet recruiting
Birmingham, Alabama, United States, 35294
Contact: Maria Loushin    212-461-2198    maria.loushin@tymeinc.com   
Principal Investigator: Ravi Paluri, MD         
United States, California
City Of Hope Recruiting
Duarte, California, United States, 91010
Contact: Isma Hafeez    626-359-8111      
Principal Investigator: Vincent Chung, MD         
Sarcoma Oncology Research Center Recruiting
Santa Monica, California, United States, 90403
Contact: Victoria Chua-Alcala, MD, CLS    310-552-9999      
Principal Investigator: Steve Wong, MD         
United States, Connecticut
Cancer Center of Central Connecticut Active, not recruiting
Southington, Connecticut, United States, 06489
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute Recruiting
Tampa, Florida, United States, 33612
Contact: Taymeyah Al-Toubah    813-745-6454    Taymeyah.al-toubah@moffitt.org   
Principal Investigator: Dae Won Kim, MD         
Florida Hospital Tampa Active, not recruiting
Tampa, Florida, United States, 33613
United States, Iowa
June E. Nylen Cancer Center Active, not recruiting
Sioux City, Iowa, United States, 51101
United States, Louisiana
University Medical Center Active, not recruiting
New Orleans, Louisiana, United States, 70112
United States, Michigan
Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Colette Zack    313-576-9385    zackc@karmanos.org   
Principal Investigator: Philip Philip, MD         
United States, Missouri
Washington University Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Megan MacDougall    314-362-5740      
Principal Investigator: Andrea Wang Gillam, MD         
United States, New York
New York Cancer and Blood Specialist Active, not recruiting
Bronx, New York, United States, 10469
North Shore Hematology Oncology Active, not recruiting
East Setauket, New York, United States, 11733
NY Cancer and Blood Specialist Active, not recruiting
East Setauket, New York, United States, 11733
NYU Langone Health Not yet recruiting
New York, New York, United States, 10016
Contact: Maria Loushin    212-461-2198    maria.loushin@tymeinc.com   
Principal Investigator: Paul Oberstein, MD         
Central Park Hematology & Oncology Active, not recruiting
New York, New York, United States, 10028
Weill Cornell Recruiting
New York, New York, United States, 10065
Contact: Chelsea Garcia    646-962-8166      
Principal Investigator: Allyson Ocean, MD         
United States, Ohio
The Ohio State University Recruiting
Columbus, Ohio, United States, 43221
Contact: Nathan Donath    614-293-4822    Nathan.Donath@osumc.edu   
Principal Investigator: Anne Noonan, MD         
United States, Texas
Texas Oncology-Baylor Active, not recruiting
Dallas, Texas, United States, 75246
MD Anderson Not yet recruiting
Houston, Texas, United States, 77030
Contact: Maria Loushin    212-461-2198    maria.loushin@tymeinc.com   
Principal Investigator: Shubham Pant, MD         
United States, Washington
Virginia Mason Medical Center Recruiting
Seattle, Washington, United States, 98101
Contact: Anas Najjar    206-287-5671      
Principal Investigator: Vincent Picozzi, MD         
Sponsors and Collaborators
Tyme, Inc
Investigators
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Study Director: Giuseppe Del Priore, MD, MPH Tyme, Inc

Additional Information:
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Responsible Party: Tyme, Inc
ClinicalTrials.gov Identifier: NCT03512756     History of Changes
Other Study ID Numbers: Tyme-88-Panc
First Posted: May 1, 2018    Key Record Dates
Last Update Posted: September 19, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Tyme, Inc:
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
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Sirolimus
Capecitabine
Everolimus
Phenytoin
Methoxsalen
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Antibiotics, Antineoplastic
Antifungal Agents
Anticonvulsants
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers