Clinical Trials /

A Study of SGT-53 in Children With Refractory or Recurrent Solid Tumors

NCT02354547

Description:

The purpose of this study is to determine the dose limiting toxicities and recommended phase 2 dose of SGT-53 alone and in combination with topotecan and cyclophosphamide in pediatric patients with recurrent or refractory solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of SGT-53 in Children With Refractory or Recurrent Solid Tumors
  • Official Title: A Phase I Study of SGT-53, a TfRscFv-Liposome-p53 Complex, in Children With Refractory or Recurrent Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: SGT53-01-2
  • NCT ID: NCT02354547

Conditions

  • Neoplasm

Interventions

DrugSynonymsArms
TopotecanHycamtinSGT-53 with Topotecan/Cyclophosphamide
CyclophosphamideCytoxan®, Neosar®SGT-53 with Topotecan/Cyclophosphamide

Purpose

The purpose of this study is to determine the dose limiting toxicities and recommended phase 2 dose of SGT-53 alone and in combination with topotecan and cyclophosphamide in pediatric patients with recurrent or refractory solid tumors.

Detailed Description

      The p53 is a vital human tumor suppressor gene. Loss of p53 suppressor function is present in
      the majority of human cancers. The p53 protein has a diverse range of functions including
      regulation of cell cycle checkpoints, cell death (apoptosis), senescence, DNA repair,
      maintenance of genomic integrity, and control of angiogenesis. Abnormalities of the p53 gene
      may impact the efficacy of standard anticancer treatments such as radiation and chemotherapy.
      P53 mutation and pathway dysfunction are associated with poor clinical outcomes and the
      presence of the p53 mutation correlates with resistance to chemotherapy and radiation. The
      development of somatic gene therapy has created the potential to restore wild type function
      of p53. SGT-53 is a complex of cationic liposome encapsulating a normal human wild type p53
      DNA sequence in a plasmid backbone. This complex has been shown to efficiently and
      specifically deliver the p53 cDNA to the tumor cells. Introduction of the p53 cDNA sequence
      is expected to restore wtp53 function in the apoptotic pathway. P53 restoration has been
      shown most effective in enhancing cytotoxicity in combination with an agent which results in
      DNA damage or initiates apoptosis. Though mutated p53 is uncommon in childhood cancer,
      children with adrenocortical tumor and rhabdomyosarcoma have been found to have p53
      mutations. Additionally, wild type p53 may be suppressed in tumors through pathway crosstalk.
      For example, in sarcomas, a common childhood solid tumor, activation of MDM2 effectively
      inactivates p53. Thus, the treatment proposed in this trial to reintroduce p53 may offer
      benefit even in patients with p53 wild-type tumors. Moreover, the SGT-53 treatment can
      significantly sensitize pediatric cancer cell lines to the killing effect of the standard
      chemotherapeutic agents, topotecan and cyclophosphamide. Thus, we propose to assess the
      efficacy of this combination therapy in pediatric patients with refractory or recurrent solid
      tumors. This phase I clinical trial is to determine the dose limiting toxicities (DLT),
      recommended phase 2 dose, and maximum tolerated dose (MTD) of SGT-53 (if reached) alone and
      in combination with conventional chemotherapy in pediatric patients with recurrent or
      refractory solid tumors. In addition, pharmacokinetics of escalating doses of SGT-53 is
      studied.
    

Trial Arms

NameTypeDescriptionInterventions
SGT-53 with Topotecan/CyclophosphamideExperimentalThere will be 4-6 cycles (21 days/cycle) of therapy in this trial. In cycle 1, SGT-53 will be given as a single agent twice weekly starting at 1.4 mg/m² of DNA per infusion to evaluate single-agent toxicity. Pharmacokinetic studies will be performed. In the absence of dose limiting toxicity, patients will proceed to cycle 2 even if they have progressive disease. Starting in cycle 2, SGT-53 will be administered twice-weekly in combination with topotecan and cyclophosphamide administered daily for 5 days, days 1-5 of each cycle. Day 1 of each combination cycle is the first day on which topotecan and cyclophosphamide are administered with SGT-53. If a subject has at least stable disease after four cycles of therapy and is tolerating protocol therapy, two additional cycles may be considered.
  • Topotecan
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          -  All patients and/or their parents or legally authorized representatives must sign a
             written informed consent.

          -  Patients must be > than 12 months and ≤ 21 years of age at the time of study
             enrollment.

          -  Body surface Area (For Dose Level -1): Patients must be ≥ 0.38 m² at the time of study
             enrollment.

          -  Patients with relapsed or refractory solid tumors (excluding primary central nervous
             system tumors) are eligible. Patients must have had histologic verification of
             malignancy at original diagnosis or relapse.

          -  Patients must have either measurable or evaluable disease.

          -  Patient's current disease state must be one for which there is no known curative
             therapy or therapy proven to prolong survival with an acceptable quality of life.

          -  Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years
             of age.

          -  Patients must have fully recovered from the acute toxic effects of all prior
             anti-cancer chemotherapy:

               -  At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if
                  prior nitrosourea).

               -  At least 14 days after the last dose of a long-acting growth factor (e.g.
                  Neulasta) or 7 days for short-acting growth factor.

               -  At least 7 days after the last dose of a biologic agent.

               -  At least 42 days after the completion of any type of immunotherapy, e.g. tumor
                  vaccines.

               -  At least 3 half-lives of the antibody after the last dose of a monoclonal
                  antibody.

               -  At least 14 days after local palliative XRT (small port); At least 150 days must
                  have elapsed if prior TBI, craniospinal XRT or if ≥ 50% radiation of pelvis; At
                  least 42 days must have elapsed if other substantial bone marrow radiation.

               -  No evidence of active graft vs. host disease and at least 84 days must have
                  elapsed after transplant or stem cell infusion.

               -  Patient must not have had prior exposure to gene vector delivery products within
                  3 months.

               -  Patients may not have had prior SGT-53. Patient who have received prior
                  topotecan, cyclophosphamide, or both are eligible.

          -  Adequate Bone Marrow Function:

               -  Peripheral absolute neutrophil count (ANC) ≥ 1000/mm³.

               -  Platelet count ≥ 100,000/mm³.

          -  Adequate Renal Function:

               -  Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m² OR age/gender
                  appropriate serum creatinine.

          -  Adequate Liver Function:

               -  Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN)
                  for age.

               -  SGPT (ALT) ≤ 110 U/L.

               -  Serum albumin ≥ 2 g/dL.

        Exclusion Criteria:

          -  Are pregnant or breast-feeding women.

          -  Concomitant medications:

               -  Patients receiving corticosteroids who have not been on a stable or decreasing
                  dose of corticosteroid for at least 7 days prior to enrollment are not eligible.

               -  Patients who are currently receiving another investigational drug are not
                  eligible.

               -  Patients who are currently receiving other anti-cancer agents are not eligible.

               -  Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
                  graft-versus-host disease post bone marrow transplant are not eligible for this
                  trial.

          -  Patients who have an uncontrolled infection are not eligible.

          -  Patients who have received a solid organ transplantation are not eligible.

          -  Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study are not eligible.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLT)
Time Frame:3-18 weeks
Safety Issue:
Description:The dose limiting toxicities of SGT-53 alone and in combination with topotecan and cyclophosphamide in pediatric patients with recurrent or refractory solid tumors will be assessed by any adverse events that are possibly, probably or definitely attributable to study drugs.

Secondary Outcome Measures

Measure:Tolerability of systemic intravenous infusion (assessed by any adverse events related to infusion of study drugs according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.)
Time Frame:3-18 weeks
Safety Issue:
Description:Tolerability of systemic intravenous infusion of SGT-53 alone and in combination with topotecan and cyclophosphamide will be assessed by any adverse events related to infusion of study drugs according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Measure:Anti-tumor activity (evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1.)
Time Frame:3-18 weeks
Safety Issue:
Description:Anti-tumor activity of SGT-53 alone and in combination with topotecan and cyclophosphamide will be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1.
Measure:Concentration of SGT-53 over time will be characterized by Cmax and clearance (Pharmacokinetic will be performed to evaluate the concentration of SGT-53 in patient's blood over time)
Time Frame:3-18 weeks
Safety Issue:
Description:Pharmacokinetic will be performed to evaluate the concentration of SGT-53 in patient's blood over time

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:SynerGene Therapeutics, Inc.

Last Updated

August 2, 2019