Clinical Trials /

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

NCT03600649

Description:

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

Related Conditions:
  • Ewing Sarcoma
  • Myxoid Liposarcoma
  • Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: SALA-002-EW16
  • NCT ID: NCT03600649

Conditions

  • 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

Interventions

DrugSynonymsArms
SeclidemstatLSD1 Inhibitor, SP-2577Ewing sarcoma, combination therapy
CyclophosphamideEwing sarcoma, combination therapy
TopotecanEwing sarcoma, combination therapy

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Myxoid LiposarcomaExperimentalTwice-daily administration of oral seclidemstat
  • Seclidemstat
Sarcomas with FET-family translocations, including demoplastic small round cell tumorsExperimentalTwice-daily administration of oral seclidemstat
  • Seclidemstat
Ewing sarcoma, combination therapyExperimentalTwice daily administration of seclidemstat in combination with cyclophosphamide and topotecan
  • Seclidemstat
  • Cyclophosphamide
  • Topotecan

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:To characterize pharmacokinetics of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide.
Measure: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
Safety Issue:
Description:To characterize pharmacokinetics of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide.
Measure: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
Safety Issue:
Description:To characterize pharmacokinetics of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide.
Measure: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
Safety Issue:
Description:To characterize pharmacokinetics of seclidemstat as a single agent and in combination with topotecan and cyclophosphamide.
Measure: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
Safety Issue:
Description:To evaluate the effect of food on the pharmacokinetics of seclidemstat. Both fasted and fed PK samples will be taken.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Salarius Pharmaceuticals, LLC

Last Updated

August 11, 2021