Clinical Trials /

A Study of BXQ-350 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) or Diffuse Midline Glioma (DMG)

NCT04771897

Description:

This study will evaluate the safety of BXQ-350 and determine the maximum tolerated dose (MTD) in children with newly diagnosed DIPG or DMG. All patients will receive BXQ-350 by intravenous (IV) infusion and radiation therapy. The study is divided into two parts: Part 1 will enroll patients at increasing dose levels of BXQ-350 in order to determine the MTD. Part 2 will enroll patients requiring a biopsy in order to assess BXQ-350 concentrations in the biopsied tumor.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
  • Diffuse Midline Glioma, H3 K27M-Mutant
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of BXQ-350 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) or Diffuse Midline Glioma (DMG)
  • Official Title: A Phase 1 Open Label, Multi-Center Study to Evaluate the Safety and Tolerability of BXQ-350 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) and Diffuse Midline Glioma (DMG)

Clinical Trial IDs

  • ORG STUDY ID: BXQ-350.AD
  • NCT ID: NCT04771897

Conditions

  • Diffuse Intrinsic Pontine Glioma
  • Diffuse Midline Glioma, H3 K27M-Mutant

Interventions

DrugSynonymsArms
BXQ-350 - Part 1 Dose Escalation: Safety and ToleranceSapC-DOPSPart 1 Dose Escalation: Safety and Tolerance
BXQ-350 - Part 2 BXQ-350 Tumor and Plasma ConcentrationsSapC-DOPSPart 2 BXQ-350 Tumor and Plasma Concentrations

Purpose

This study will evaluate the safety of BXQ-350 and determine the maximum tolerated dose (MTD) in children with newly diagnosed DIPG or DMG. All patients will receive BXQ-350 by intravenous (IV) infusion and radiation therapy. The study is divided into two parts: Part 1 will enroll patients at increasing dose levels of BXQ-350 in order to determine the MTD. Part 2 will enroll patients requiring a biopsy in order to assess BXQ-350 concentrations in the biopsied tumor.

Detailed Description

      BXQ-350 is a novel anti-neoplastic therapeutic agent configured from two components: Saposin
      C (SapC), an expressed (human) lysosomal protein, and the phospholipid
      dioleoylphosphatidyl-serine (DOPS), a cell membrane phospholipid (clinical formulation
      BXQ-350). Given via intravenous IV, data indicate that the agent exhibits the propensity to
      enter the body and brain, target cells in the tumor mass, and induce cell death. DIPG and DMG
      present a treatment dilemma due to resistance to standard therapy (radiotherapy) and
      aggressive clinical course. The use of BXQ-350 provides a novel approach to the treatment of
      cancer through interaction with the cancer cell membrane. This drug appears to be well
      tolerated in previous clinical trials, and in combination with the standard of care radiation
      therapy, may help improve overall survival in these patients.

      The study is divided into 2 parts:

      Part 1: Dose Escalation and Safety - Sequential cohorts of patients 1-30 years of age with
      newly diagnosed DIPG or DMG will be treated with escalating doses of BXQ-350 until the MTD is
      established, or in the absence of a Maximum Administered Dose, the highest planned dose level
      is reached.

      Part 2: BXQ-350 Tumor and Plasma Concentrations - Patients undergoing neurosurgical biopsy
      prior to receiving radiation therapy will be enrolled and receive BXQ-350 at the MTD
      determined in Part 1, or at the highest planned dose level, and radiation therapy. Excised
      tumor tissue will be evaluated for SapC levels and pharmacodynamic effects.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1 Dose Escalation: Safety and ToleranceExperimentalSequential cohorts of patients with newly diagnosed DIPG or DMG will be treated with escalating doses of BXQ-350 until the maximum tolerated dose (MTD) is established, or in the absence of a maximum administered dose (MAD), the highest planned dose level is reached and radiation therapy.
  • BXQ-350 - Part 1 Dose Escalation: Safety and Tolerance
Part 2 BXQ-350 Tumor and Plasma ConcentrationsExperimentalNewly diagnosed DIPG or DMG patients undergoing neurosurgical biopsy prior to receiving radiation therapy will receive BXQ-350 at the MTD established in Part 1, or the highest planned dose level, and radiation therapy. Excised tumor tissue and plasma samples will be evaluated for SapC levels and pharmacodynamic effects.
  • BXQ-350 - Part 2 BXQ-350 Tumor and Plasma Concentrations

Eligibility Criteria

        Inclusion Criteria:

        Each subject must meet the following criteria:

          1. Provide signed, written informed consent prior to the initiation of any study-specific
             procedures (consent from guardians for minor children and patient assent according to
             institution and Institutional Review Board (IRB) standards)

          2. Age ≥ 1 year of age and ≤ 30 years of age at the time of study entry

          3. Have radiographically suspected or histologically confirmed newly diagnosed DIPG or
             DMG with the following defining disease characteristics/features:

               -  Part 1 and Part 2:

                    -  DIPG: radiographic imaging showing a diffuse expansion of the brainstem/pons
                       by a tumor that is poorly defined but abnormally bright in signal on
                       T2-weighted images and abnormally dark on T1-weighted images; contrast
                       enhancement, when present, is typically mild; there may be some indication
                       of necrosis, and the basilar artery is commonly engulfed by tumor.

                    -  DMG: the same imaging characteristics as noted above for DIPG are present,
                       but the lesion can extend superiorly up into the midbrain and thalami,
                       and/or inferiorly to the medulla.

                    -  In cases of disease that is not classic for DIPG or DMG, biopsy may be
                       necessary in order to obtain histological confirmation of eligibility.

               -  Part 2: newly-diagnosed DIPG or DMG planning to undergo biopsy at the
                  recommendation of the treating physician; to be considered evaluable for PK
                  tissue concentration analysis, tumor samples must have at least 50% viable tumor
                  cells with <30% necrosis or hemorrhage as determined by the study
                  neuropathologist

          4. If receiving glucocorticoid therapy: dexamethasone allowed with maximum allowable dose
             16mg/day

          5. Have measurable or non-measurable disease per RANO criteria

          6. Have Lansky (age 1 - 15) / Karnofsky (age ≥ 16) Performance Score of ≥ 50% or Eastern
             Cooperative Oncology Group (ECOG) Performance Status (age ≥ 18) of 0 - 2

               -  Subjects unable to walk because of paralysis, but who can sit without
                  assistance/restraint and control a wheelchair, will be considered ambulatory for
                  the purpose of assessing the performance score

          7. Have acceptable liver function defined as:

               -  Total serum bilirubin ≤ 1.5 x upper limit of normal for the study site (ULN) (in
                  subjects with known Gilbert Syndrome, total bilirubin ≤ 3 x ULN, with direct
                  bilirubin ≤ 1.5 x ULN)

               -  Aspartate Transaminase (AST), Serum Glutamic Oxaloacetic Transaminase (SGOT),
                  Alanine Transaminase (ALT), Serum Glutamic-Pyruvic Transamine (SGPT) ≤ 3 x ULN
                  (if liver metastases are present, then ≤ 5 x ULN is allowed)

               -  Serum albumin ≥ 3 grams/deciliter (g/dL)

          8. Have acceptable renal function defined as:

               -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥70
                  milliliters (mL)/min/1.73 meters squared (m2) or a serum creatinine based on
                  age/gender as follows: 1 to < 2 years: 0.6 (male); 0.6 (female) 2 to < 6 years:
                  0.8 (male); 0.8 (female) 6 to < 10 years: 1 (male); 1 (female) 10 to < 13 years:
                  1.2 (male); 1.2 (female) 13 to < 16 years: 1.5 (male); 1.4 (female)

                    -  16 years: 1.7 (male);1.4 (female)

                         -  Threshold creatinine values derived from the Schwartz formula for
                            estimating GFR utilizing child length and stature data published by the
                            Center for Disease Control (Schwartz 2009)

          9. Have acceptable bone marrow function defined as:

               -  Absolute neutrophil count (ANC) ≥ 1,500 cells/ cubic millimeter (mm3)

               -  Platelet count ≥ 100,000 cells/mm3 (unsupported, no transfusion within 7 days of
                  enrollment)

               -  Hemoglobin > 9.0 g/dL (unsupported, no transfusion within 7 days of enrollment)

         10. Have acceptable coagulation parameters (anti-coagulation allowed) defined as:

               -  International normalized ratio (INR) ≤ 2 x ULN unless on anticoagulation or
                  prothrombin time (PT) within normal limits

               -  Activated partial thromboplastin time (aPTT) within normal limits

         11. Have a negative serum pregnancy test result at screening (for females of child bearing
             potential (FCBP); not applicable to subjects who are unable to become pregnant,
             including those with tubal ligation, bilateral oophorectomy and/or hysterectomy,
             post-menopausal is defined as > 12 months since last menstrual cycle)

         12. FCBP and male subjects whose sexual partner(s) are FCBP must agree to abstain from
             heterosexual activity or use a double barrier method of contraception (e.g., condom
             and occlusive cap with spermicide) or highly effective contraception (intrauterine
             device or system, established hormonal contraceptive methods on a stable dose from the
             time of the last menstrual cycle, or vasectomized partner with confirmed azoospermia)
             from the time of study entry to 1 month after the last day of treatment

        Exclusion Criteria:

        Subjects must not meet any of the following criteria:

          1. Have a concurrent or secondary malignancy

          2. Have a low-grade glioma (Grade II or less)

          3. Have received prior treatment with radiation, chemotherapy, anti-neoplastic, or
             investigational agents

          4. Have had major surgery other than a minor outpatient procedure within 28 days prior to
             dose assignment or have not recovered from major side effects of the surgery if more
             than 4 weeks have elapsed since surgery

          5. Have poorly controlled hypertension despite the use of antihypertensive agents defined
             as blood pressure ≥95th percentile for age and weight or >160/90 on at least 2
             repeated determinations on separate days within 2 weeks (14 days) prior to initiation
             of screening

          6. Have a history of cardiac dysfunction including:

               -  myocardial infarction within 6 months prior to initiation of screening

               -  history of documented congestive heart failure (New York Heart Association
                  functional classification III-IV) within 6 months prior to initiation of
                  screening

               -  active cardiomyopathy

               -  electrocardiogram (ECG) with QTc >470 msec at screening

               -  echocardiogram with ejection fraction <50% or a decrease in the left ventricular
                  shortening fraction to <27%

          7. Have a known history of Human Immunodeficiency Virus (HIV) seropositivity

          8. Have active (acute or chronic) or uncontrolled severe infections

          9. Have active poor wound healing (delayed healing, wound infection or fistula)

         10. Have evidence of active clinically significant bleed (e.g., gastrointestinal bleed,
             hemoptysis, or gross hematuria) at screening

         11. Are pregnant or nursing, where pregnancy is defined as the state of a female after
             conception and until the termination of gestation, confirmed by a positive serum human
             chorionic gonadotropin (hCG) laboratory test

         12. Have a known sensitivity to any component of BXQ-350

         13. Have other concurrent severe and/or uncontrolled medical condition that would, in the
             Principal Investigator's judgment contraindicate the subject's participation in the
             clinical study or obscure assessment of toxicity
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment Emergent Adverse Events as Assessed by CTCAE v5.0
Time Frame:12 months
Safety Issue:
Description:To determine the safety of BXQ-350 in children with newly diagnosed DIPG or DMG, as evidenced by the incidence of treatment emergent adverse events assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:12 months
Safety Issue:
Description:To determine the ORR of BXQ-350 when given with radiation therapy in children with newly diagnosed DIPG or DMG. ORR is defined as the percentage of participants with evidence of a complete or partial response as per the Response Assessment in Neuro-Oncology (RANO) criteria.
Measure:Overall Survival (OS)
Time Frame:12 months
Safety Issue:
Description:To evaluate OS in children with newly diagnosed DIPG or DMG receiving BXQ-350 with radiation therapy. OS is defined as the time from initiation of therapy to death from any cause. Participants still alive will be censored at the date of the last contact.
Measure:Quality of Life (QoL)
Time Frame:12 months
Safety Issue:
Description:To evaluate QoL in children with newly diagnosed DIPG or DMG receiving BXQ-350 with radiation therapy. QoL will be measured utilizing the Patient-Reported Outcomes Measurement Information System (PROMIS) in participants 5 years of age or older. PROMIS measures use a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation. A higher score equals more of the concept being measured (i.e. more fatigue, more physical function, etc.). This could be a desirable or undesirable outcome, depending on the concept being measured.
Measure:Concentration of drug at steady state (Css)
Time Frame:12 months
Safety Issue:
Description:To assess exposure to BXQ-350 in children with newly diagnosed DIPG or DMG receiving BXQ-350 with radiation therapy. Exposure will be measured utilizing pharmacokinetic parameter of concentration of drug at steady state (Css).
Measure:Exposure to BXQ-350 - area under the curve (AUC)
Time Frame:12 months
Safety Issue:
Description:To assess exposure to BXQ-350 in children with newly diagnosed DIPG or DMG receiving BXQ-350 with radiation therapy. Exposure will be measured utilizing pharmacokinetic parameter of area under the curve (AUC).
Measure:Exposure to BXQ-350 - clearance (CL)
Time Frame:12 months
Safety Issue:
Description:To assess exposure to BXQ-350 in children with newly diagnosed DIPG or DMG receiving BXQ-350 with radiation therapy. Exposure will be measured utilizing pharmacokinetic parameter of clearance (CL).
Measure:Exposure to BXQ-350 - volume of distribution (Vd)
Time Frame:12 months
Safety Issue:
Description:To assess exposure to BXQ-350 in children with newly diagnosed DIPG or DMG receiving BXQ-350 with radiation therapy. Exposure will be measured utilizing pharmacokinetic parameter of volume of distribution (Vd).
Measure:Exposure to BXQ-350 - half-life (t½)
Time Frame:12 months
Safety Issue:
Description:To assess exposure to BXQ-350 in children with newly diagnosed DIPG or DMG receiving BXQ-350 with radiation therapy. Exposure will be measured utilizing pharmacokinetic parameter of volume of half-life (t½).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Bexion Pharmaceuticals, Inc.

Trial Keywords

  • DIPG
  • DMG
  • brain tumor
  • glioma

Last Updated

March 1, 2021