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Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing Sarcoma

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ClinicalTrials.gov Identifier: NCT03600649
Recruitment Status : Recruiting
First Posted : July 26, 2018
Last Update Posted : February 11, 2019
Sponsor:
Information provided by (Responsible Party):
Salarius Pharmaceuticals, LLC

Brief Summary:
Phase 1, open-label, non-randomized dose finding study of SP-2577 in patients with refractory or recurrent Ewing sarcoma.

Condition or disease Intervention/treatment Phase
Ewing Sarcoma Drug: SP-2577 Phase 1

Detailed Description:
This phase 1 study is an open-label, non-randomized dose escalation study of SP-2577 administered orally in patients with refractory or recurrent Ewing sarcoma. The study design is based on a Simon's 4B design.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This single arm study will utilize an accelerated dose escalation, followed by a conventional 3+3 dose escalation phase to achieve maximum tolerated dose (MTD).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Trial of the LSD1 Inhibitor SP-2577 in Patients With Relapsed or Refractory Ewing Sarcoma
Actual Study Start Date : June 4, 2018
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : August 2020


Arm Intervention/treatment
Experimental: SP-2577 Drug: SP-2577
Dose escalation and dose expansion of SP-2577
Other Name: LSD1 Inhibitor




Primary Outcome Measures :
  1. Incidence of treatment-emergent side effects [ Time Frame: From screening through at least 30 days after end of treatment, up to approximately 24 months ]
    Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0


Secondary Outcome Measures :
  1. Maximum tolerated dose (MTD) of SP-2577 [ Time Frame: DLTs within the first cycle of therapy (up to 28 days) ]
    Defined as the dose level immediately below the dose level at which ≥ 2 patients from a cohort of 3 to 6 patients experience a dose-limiting toxicity (DLT).

  2. Pharmacokinetic parameter: area under the concentration time profile of SP-2577 under fasted and fed conditions [ Time Frame: At protocol defined time points on cycle 1 (each cycle is 28 days), day 1 and 2 and cycle 2, day 1 and 2. ]
  3. Pharmacokinetic parameter: time to maximum plasma concentration of SP-2577 under fasted and fed conditions [ Time Frame: At protocol defined time points on cycle 1 (each cycle is 28 days), day 1 and 2 and cycle 2, day 1 and 2. ]
  4. Pharmacokinetic parameter: maximum plasma concentration of SP-2577 under fasted and fed conditions [ Time Frame: At protocol defined time points on cycle 1 (each cycle is 28 days), day 1 and 2 and cycle 2, day 1 and 2. ]
  5. Pharmacokinetic parameter: half-life of SP-2577 under fasted and fed conditions [ Time Frame: At protocol defined time points on cycle 1 (each cycle is 28 days), day 1 and 2 and cycle 2, day 1 and 2. ]
  6. Pharmacokinetic parameter: clearance rate of SP-2577 under fasted and fed conditions [ Time Frame: At protocol defined time points on cycle 1 (each cycle is 28 days), day 1 and 2 and cycle 2, day 1 and 2. ]
  7. Pharmacokinetic parameter: volume of distribution of SP-2577 under fasted and fed conditions [ Time Frame: At protocol defined time points on cycle 1 (each cycle is 28 days), day 1 and 2 and cycle 2, day 1 and 2. ]
  8. Efficacy parameter: overall response rate of SP-2577 [ Time Frame: From start of treatment through at least 30 days after end of treatment, up to approximately 24 months ]
    Assessed by radiographic imaging with response and progression evaluated by RECIST 1.1 guidelines

  9. Efficacy parameter: duration of response of SP-2577 [ Time Frame: From start of treatment through at least 30 days after end of treatment, up to approximately 24 months ]
    Assessed by radiographic imaging with response and progression evaluated by RECIST 1.1 guidelines

  10. Efficacy parameter: progression-free survival of SP-2577 [ Time Frame: From start of treatment through at least 30 days after end of treatment, up to approximately 24 months ]
    Assessed by radiographic imaging with response and progression evaluated by RECIST 1.1 guidelines and vital status information


Other Outcome Measures:
  1. Changes in circulating tumor cells (CTCs) number [ Time Frame: At protocol defined time points from start of treatment through end of treatment, up to approximately 24 months ]
    Assessed by changes in CTC number correlated with SP-2577 treatment and clinical and radiographic markers of disease burden (either response or resistance/progression).

  2. Changes in circulating tumor cells (CTCs) RNA sequencing profiles [ Time Frame: At protocol defined time points from start of treatment through end of treatment, up to approximately 24 months ]
    Assessed by changes in the RNA sequencing profiles correlated with SP-2577 treatment and clinical and radiographic markers of disease burden (either response or resistance/progression).

  3. Changes in cell-free DNA (cfDNA) [ Time Frame: At protocol defined time points from start of treatment through end of treatment, up to approximately 24 months ]
    Determine changes in cfDNA levels correlated with SP-2577 treatment and clinical and radiographic markers of disease burden (either response or resistance/progression).

  4. Changes in serum hemoglobin F concentrations [ Time Frame: At protocol defined time points from start of treatment through end of treatment, up to approximately 24 months ]
    Determine changes serum hemoglobin F concentrations correlated with SP-2577 treatment and clinical and radiographic markers of disease burden (either response or resistance/progression).

  5. Changes in the molecular signatures of the tumor [ Time Frame: At protocol defined time points from start of treatment through end of treatment, up to approximately 24 months ]
    Assessed in dose expansion only by RNA-seq testing of tumor biopsy samples to determine changes in gene expression patterns by SP-2577 treatment to elucidate biological changes induced in the tumor by LSD1 inhibition.



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a histologic confirmed diagnosis of Ewing sarcoma that is refractory or recurrent and must have received at least one prior course of therapy for Ewing sarcoma. For the purposes of this study, refractory disease is defined as metastatic or unresectable disease that has either progressed or is stable at completion of planned therapy.
  • Patients must have radiographic evidence of disease. Patients must have disease evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Bone only disease that has been biopsy-proven is acceptable during dose escalation but not expansion phase.
  • Patients must have had prior camptothecin-based regimen, have a contraindication to camptothecin-based regimen, or declined treatment with a camptothecin-based regimen.
  • Age ≥ 12 years and weight ≥ 40 kg.
  • Karnofsky ≥70% for over ≥16 years old and Lansky ≥70% for under 16 years old, see Appendix A, equivalent to Eastern Cooperative Oncology Group (ECOG) performance status grade 0 or 1
  • Life expectancy of greater than 4 months.
  • Patients must have normal organ and marrow function
  • Archival tumor tissue available for translocation analysis or willingness to provide tumor biopsy during screening.
  • Willingness to provide tumor biopsies on and off treatment (Tier 2: Dose expansion cohort only). Optional for patients <18 years of age.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Patients who have not recovered to grade 1 or baseline from adverse events related to prior therapy excluding lymphopenia, alopecia, peripheral neuropathy and ototoxicity, which are excluded if ≥ CTCAE grade 3.
  • Patients who are receiving any other investigational agents.
  • Prior therapy with LSD1 targeted agents including monoamine oxidases for cancer therapy.
  • Prior systemic anti-cancer treatment (chemotherapy, biologic therapy [ie. small molecular inhibitors, monoclonal antibodies]) within 21 days prior to Cycle 1 Day 1. For agents that have known adverse events occurring beyond 21 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
  • Prior therapy with immunotherapy such as a checkpoint inhibitor, cellular therapy or vaccine within 42 days prior to Cycle 1 Day 1
  • Prior small port palliative radiotherapy within 14 days or 42 days from definitive local control radiation (any dose greater than 50Gy).
  • Prior therapy with long acting myeloid growth factor within 14 days or 7 days from a short acting myeloid growth factor.
  • Evidence of graft versus host disease or prior allo- or auto-bone marrow transplant (BMT) or stem cell infusion within 84 days from Cycle 1 Day 1 or receiving immunosuppression following a stem cell procedure.
  • Participation in a prior investigational study within 30 days prior to Cycle 1 Day 1 or within 5-half-lives of the investigational product, whichever is longer.
  • Patients with progressive or symptomatic brain metastases. Patients with brain metastases may be included in this trial as long as the brain metastases have received definitive treatment and are stable (i.e., no evidence of progression). The brain metastases must be stable for a minimum of 6 weeks.
  • Patients currently receiving any of the following substances and cannot be discontinued 14 days prior to Cycle 1 Day 1:

    • Moderate or strong inhibitors or inducers of major CYP isoenzymes, including grapefruit, grapefruit hybrids, pomelos, star-fruit, and Seville oranges
    • Moderate or strong inhibitors or inducers of major drug transporters
    • Substrates of CYP3A4/5 with a narrow therapeutic index
  • Uncontrolled concurrent illness including, but not limited to:

    • ongoing or active infection
    • transfusion dependent thrombocytopenia or anemia
    • psychiatric illness/social situations that would limit compliance with study requirements
  • Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:

    • symptomatic congestive heart failure
    • Left Ventricular Ejection Fraction (LVEF) ≤ 50%
    • unstable angina pectoris or cardiac arrhythmia
    • baseline QTc ≥ 450 milliseconds
    • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome
  • Any major surgery within 21 days prior to Cycle 1 Day 1.
  • Pregnant and breastfeeding women are excluded from this study. The effects of SP-2577 on the developing human fetus have the potential for teratogenic or abortifacient effects. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SP-2577.
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of SP-2577 administration.
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with SP-2577. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.

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): NCT03600649


Contacts
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Contact: David S Wages, MD,PhD 508-740-7500 dwages@salariuspharma.com

Locations
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United States, California
Childrens Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Leo Mascarhenas, MD         
Contact: Magnolia Manzano         
United States, Florida
Johns Hopkins All Children's Hospital Recruiting
Saint Petersburg, Florida, United States, 33701
Contact: Jessica Crimella         
Principal Investigator: Jonathan Metts, MD         
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Tiffany Smith, MS, CRC         
Principal Investigator: Damon Reed, MD         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Morgan Krush         
Principal Investigator: Steven Dubois, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Douglas Harrison, MD         
Contact: Sherry Melton         
Sponsors and Collaborators
Salarius Pharmaceuticals, LLC
Investigators
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Principal Investigator: Damon Reed, MD Moffitt Cancer Center

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Responsible Party: Salarius Pharmaceuticals, LLC
ClinicalTrials.gov Identifier: NCT03600649     History of Changes
Other Study ID Numbers: SALA-002-EW16
First Posted: July 26, 2018    Key Record Dates
Last Update Posted: February 11, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Sarcoma
Sarcoma, Ewing
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue