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

• ClinicalTrials.gov Identifier: NCT03600649
• Recruitment Status: Active, not recruiting
• First Posted: July 26, 2018
• Last Update Posted: November 21, 2023
• Sponsor: Salarius Pharmaceuticals, LLC
• Collaborator: National Pediatric Cancer Foundation
• Information provided by (Responsible Party): Salarius Pharmaceuticals, LLC

Tracking Information

• First Submitted Date: June 4, 2018
• First Posted Date: July 26, 2018
• Last Update Posted Date: November 21, 2023
• Actual Study Start Date: June 4, 2018
• Estimated Primary Completion Date: September 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 12, 2021)

Safety and tolerability of seclidemstat (SP-2577) as a single agent and in combination with topotecan and cyclophosphamide measured by dose limiting toxicities and adverse events according to CTCAE version 5.0 [ Time Frame: From screening through at least 30 days after end of treatment, up to approximately 24 months ]

To evaluate the safety and tolerability of seclidemstat (SP-2577) as a single agent and in combination with topotecan and cyclophosphamide in patients with relapsed or refractory Ewing sarcoma and select sarcomas. Toxicities will be graded in severity per the guidelines outlined in the NCI CTCAE version 5.0. The maximum tolerated dose (MTD) is 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.

Original Primary Outcome Measures (submitted: July 19, 2018)

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

Current Secondary Outcome Measures (submitted: April 12, 2021)

• Determine the maximum tolerated dose of SP-2577 as determined by dose limiting toxicities measured according to CTCAE version 5.0 [ Time Frame: From screening through at least 30 days after end of treatment, up to approximately 24 months ]
  To determine the maximum tolerated dose (MTD) of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide in patients with relapsed or refractory Ewing sarcoma. Toxicities will be graded in severity per the guidelines outlined in the NCI CTCAE version 5.0. The maximum tolerated dose (MTD) is 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.
• Characterization of the pharmacokinetics of SP-2577 as measured by peak plasma concentration [ Time Frame: From screening through at least 30 days after end of treatment, up to approximately 24 months ]
  To characterize pharmacokinetics of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide.
• Characterization of the pharmacokinetics of SP-2577 as measured by area under the curve [ Time Frame: From screening through at least 30 days after end of treatment, up to approximately 24 months ]
  To characterize pharmacokinetics of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide.
• Characterization of the pharmacokinetics of SP-2577 as measured by apparent clearance of seclidemstat [ Time Frame: From screening through at least 30 days after end of treatment, up to approximately 24 months ]
  To characterize pharmacokinetics of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide.
• Characterization of the pharmacokinetics of SP-2577 as measured by median half-life [ Time Frame: From screening through at least 30 days after end of treatment, up to approximately 24 months ]
  To characterize pharmacokinetics of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide.
• Food effects on the pharmacokinetics of SP-2577 as measured in both fasted and fed populations, primarily measured by apparent clearance. [ Time Frame: From screening through at least 30 days after end of treatment, up to approximately 24 months ]
  To evaluate the effect of food on the pharmacokinetics of seclidemstat. Both fasted and fed PK samples will be taken.
• Anti-tumor activity as measured according to RECIST 1.1 criteria based upon radiological assessments. [ Time Frame: From screening through at least 30 days after end of treatment, up to approximately 24 months ]
  To evaluate the anti-tumor activity of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide. Tumor response will be measured according to RECIST 1.1 criteria. Radiological assessments may be centrally collected and subjected to quality checks and review by a central imaging vendor at the discretion of Salarius.

Original Secondary Outcome Measures (submitted: July 19, 2018)

• 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).
• 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. ]
• 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. ]
• 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. ]
• 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. ]
• 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. ]
• 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. ]
• 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
• 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
• 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

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: July 19, 2018)

• 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).
• 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).
• 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).
• 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).
• 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.

Descriptive Information

• Brief Title: Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
• Official Title: Phase 1 Trial of the LSD1 Inhibitor Seclidemstat (SP 2577) With and Without Topotecan and Cyclophosphamide in Patients With Relapsed or Refractory Ewing Sarcoma and Select Sarcomas
• Brief Summary: Single agent, non-randomized, open label expansion in select sarcoma patients including myxoid liposarcoma and other sarcomas that share similar chromosomal translocations to Ewing sarcoma; AND dose expansion of the combination of seclidemstat with topotecan and cyclophosphamide in patients with Ewing sarcoma

Detailed Description

The single agent expansion cohort of select sarcoma patients will enroll myxoid liposarcoma patients and patients with other sarcomas that share similar chromosomal translocations to Ewing sarcoma (FET-family translocations), including but not limited to desmoplastic small round cell tumor.

A safety lead-in dose escalation and dose expansion will be conducted assessing the combination of seclidemstat with topotecan and cyclophosphamide in patients with relapsed or refractory Ewing sarcoma.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Two cohorts with single-agent seclidemstat in patients with myxoid liposarcoma and in patients with other sarcomas with similar chromosomal translocations to Ewing sarcoma (FET-family translocations), and one cohort of Ewing sarcoma patients treated with seclidemstat in combination with topotecan and cyclophosphamide

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Ewing Sarcoma
• Myxoid Liposarcoma
• Sarcoma,Soft Tissue
• Desmoplastic Small Round Cell Tumor
• Extraskeletal Myxoid Chondrosarcoma
• Angiomatoid Fibrous Histiocytoma
• Clear Cell Sarcoma
• Primary Pulmonary Myxoid Sarcoma
• Myoepithelial Tumor
• Sclerosing Epithelioid Fibrosarcoma
• Fibromyxoid Tumor

Intervention

• Drug: Seclidemstat
  Twice daily administration of seclidemstat
  Other Names:

  • LSD1 Inhibitor
  • SP-2577
• Drug: Cyclophosphamide
  250 mg/m2/day on Days 1 thru 5 of a 21-day cycle
• Drug: Topotecan
  0.75 mg/m2/day on Days 1 thru 5 of a 21-day cycle

Study Arms

• Experimental: Myxoid Liposarcoma
  Twice-daily administration of oral seclidemstat
  Intervention: Drug: Seclidemstat
• Experimental: Sarcomas with FET-family translocations, including demoplastic small round cell tumors
  Twice-daily administration of oral seclidemstat
  Intervention: Drug: Seclidemstat
• Experimental: Ewing sarcoma, combination therapy
  Twice daily administration of seclidemstat in combination with cyclophosphamide and topotecan
  Interventions:

  • Drug: Seclidemstat
  • Drug: Cyclophosphamide
  • Drug: Topotecan

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 19, 2018): 50
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: September 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria for All Patients

• Age ≥ 12 years and weight ≥ 40 kg.
• Karnofsky ≥ 70% for over ≥ 16 years old and Lansky ≥ 70% for under 16 years old, equivalent to Eastern Cooperative Oncology Group (ECOG) performance status Grade 0 or 1.
• Life expectancy of greater than 4 months in investigator's opinion.
• Willingness to provide tumor biopsies during screening and while on treatment. Optional for patients < 18 years of age and patients enrolled in the Ewing sarcoma combination treatment arm. Biopsies can be exempt if deemed by the investigator that the biopsy is not medically feasible for the patient or the patient is unfit for the procedure.

• Normal organ and marrow function as defined below:

  • absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • platelets ≥ 100 x 109/L; no transfusion 7 days prior to labs
  • total bilirubin ≤ 1.5 x upper limit of normal (ULN) or, in patients with Gilbert syndrome, total bilirubin > 1.5 x ULN as long as direct bilirubin is normal
  • AST and ALT ≤ 3 x ULN
  • creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above normal
• Ability to understand and the willingness to sign a written informed consent document.

Additional Inclusion Criteria for Ewing Sarcoma Combination Treatment Cohort

• Patients must have a histologic confirmed diagnosis of Ewing sarcoma with a known EWSR1 translocation through local assessment that is relapsed or refractory 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 had no more than 2 lines/courses of systemic treatment for Ewing sarcoma
• No prior therapy with the combination regimen of topotecan and cyclophosphamide. Prior cyclophosphamide is allowed if not combined with topotecan.
• Patients must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Additional Inclusion Criteria for Single Agent Myxoid Liposarcoma Cohort and for Single Agent FET-Translocated Sarcomas

• Patients must have a histologic confirmed diagnosis of one of the following sarcomas that share similar known chromosomal translocations to Ewing sarcoma (per local assessment) and are relapsed or refractory and not amenable to surgery at time of enrollment.
• Patients must have received at least one prior course of systemic therapy but no more than 3 courses of systemic therapy for sarcoma.
• Patients must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Exclusion Criteria for All Patients

• 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 only exclusionary if original AE was ≥ CTCAE Grade 3.
• Patients receiving therapy with other anti-neoplastic or experimental agents.
• Prior therapy with LSD1 targeted agents including monoamine oxidases for cancer therapy.
• Prior oral tyrosine kinase inhibitors (i.e. sorafenib, pazopanib, regorafenib, cabozantanib) within 14 days of Cycle 1 Day 1.
• Other, prior systemic anti-cancer treatment (chemotherapy or biologic therapy [i.e. 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 Medical Monitor.
• Prior therapy with immunotherapy such as a checkpoint inhibitor, cellular therapy or vaccine therapy within 28 days prior to Cycle 1 Day 1. Patients must have recovered from any immune-related adverse events to Grade 1 or baseline and require ≤ 10 mg of prednisone equivalent daily. Patients with immune-related hypothyroidism and/or hypoadrenalism may enroll while on thyroid or hydrocortisone replacement therapy, respectively.
• Prior small port palliative radiotherapy within 14 days of Cycle 1 Day 1 or within 42 days of Cycle 1 Day 1 from definitive local control radiation (any dose greater than 50 Gy, within 42 days of Cycle 1 Day 1).
• Prior therapy with long acting myeloid growth factor within 14 days of Cycle 1 Day 1 or within 7 days of Cycle 1 Day 1 from a short acting myeloid growth factor.
• Evidence of graft versus host disease or prior allo- or auto-bone marrow transplant or stem cell infusion within 84 days from Cycle 1 Day 1 or receiving immunosuppressants 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.
• 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 prior to Cycle 1 Day 1.

• Currently receiving any of the following substances and cannot be discontinued 14 days or 5 half-lives for CYP inhibitors (whichever is shorter) 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; discuss with Medical Monitor if there are any questions

• 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 (Fridericia) ≥ 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. Major surgery is defined as any significantly invasive procedure into a major body cavity (abdomen, cranium etc.) and/or surgery requiring extensive recuperation (joint replacement). Please discuss with Medical Monitor if there are any questions.
• Pregnant and breastfeeding women are excluded from this study. The effects of seclidemstat on the developing human fetus have the potential for teratogenic or abortifacient effects.
• 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 seclidemstat administration.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with seclidemstat. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03600649
• Other Study ID Numbers: SALA-002-EW16
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Salarius Pharmaceuticals, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Salarius Pharmaceuticals, LLC
• Original Study Sponsor: Same as current
• Collaborators: National Pediatric Cancer Foundation
• Investigators: Not Provided
• PRS Account: Salarius Pharmaceuticals, LLC
• Verification Date: November 2023