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Testing the Safety and Tolerability of CX-4945 in Patients With Recurrent Medulloblastoma Who May or May Not Have Surgery

NCT03904862

Description:

This is a multi center, Phase I, Phase II and surgical study of the CX-4945 drug (silmitasertib sodium) for patients with recurrent SHH (Sonic Hedgehog) medulloblastoma

Related Conditions:
  • Medulloblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Safety and Tolerability of CX-4945 in Patients With Recurrent Medulloblastoma Who May or May Not Have Surgery
  • Official Title: PBTC-053: A Pediatric Brain Tumor Consortium Phase I/ II and Surgical Study of CX-4945 in Patients With Recurrent SHH Medulloblastoma

Clinical Trial IDs

  • ORG STUDY ID: PBTC-053
  • SECONDARY ID: 5UM1CA081457
  • NCT ID: NCT03904862

Conditions

  • Medulloblastoma, Childhood

Interventions

DrugSynonymsArms
CX 4945Silmitasertib sodiumPhase I - Skeletally-immature

Purpose

This is a multi center, Phase I, Phase II and surgical study of the CX-4945 drug (silmitasertib sodium) for patients with recurrent SHH (Sonic Hedgehog) medulloblastoma

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D)
      of CX-4945 administered orally daily to skeletally-immature children with recurrent SHH
      (sonic hedgehog) medulloblastoma (Phase I) II. To describe the toxicity profile and define
      the dose-limiting toxicities (DLTs) of CX-4945 in skeletally-immature children with recurrent
      SHH (sonic hedgehog) medulloblastoma. (Phase I) III. To characterize the pharmacokinetics of
      CX-4945 administered orally daily to skeletally-immature children with recurrent SHH (sonic
      hedgehog) medulloblastoma. (Phase I) IV. To characterize the concentrations of CX-4945 in
      tumor after administration of CX-4945 and surgical resection (Surgical Study). V. To
      establish the safety and characterize the toxicity of 1000mg BID continuous dosing of CX-4945
      in skeletally-mature patients with recurrent SHH medulloblastoma (Phase II). VI. To estimate
      the objective response rate associated with CX-4945 in skeletally-mature patients with
      recurrent SHH medulloblastoma

      SECONDARY OBJECTIVES:

      I. To document preliminary antitumor activity of CX-4945 in skeletally-immature children with
      recurrent SHH medulloblastoma (Phase I). II. To perform a genomic analysis within the
      confines of a Phase I study to investigate correlation between response to treatment and the
      presence of specific genomic alterations. and/or specific subgroups of disease (Phase I).
      III. To explore the ability of CX-4945 at the MTD/ RP2D to inhibit CK2-mediated signaling in
      tumor (Surgical Study). IV. To characterize the pharmacokinetics of CX-4945 in
      skeletally-mature patients with recurrent SHH medulloblastoma (Phase II). V. To perform a
      genomic analysis within the confines of a Phase II study to investigate correlation between
      response to treatment and the presence of specific genomic alterations and/or specific
      subgroups of disease (Phase II).

      OUTLINE: Phase I component is a dose-escalation study. The Phase II component is to establish
      the safety of 1000mg BID given continuously.

      The study will open with a safety cohort of 3 subjects who are considered skeletally-mature.
      The initial 3 subjects will be administered CX-4945 twice a day at the adult RP2D of 1000 mg
      BID or at its BSA adjusted equivalent; however, the dose will be given continuously. If there
      are not excessive toxicities in this cohort, the study will proceed following the Phase II
      design for subjects who are skeletally-mature.

      Following the safety lead in, the Phase 1 component of this trial will be initiated.
      Skeletally-immature children with refractory or recurrent medulloblastoma of the SHH
      subgroup, will be administered CX-4945 twice a day on a continuous basis at a starting dose
      of 600mg/m2 BID which corresponds approximately to the BSA adjusted recommended Phase 2 dose
      (RP2D) of 1000mg. The Phase 1 study will escalate doses to determine the maximum tolerated
      dose skeletally-immature children.

      The surgical study will be initiated after the first 3 patients in the skeletally-mature
      cohort are treated for initial assessment of safety and did not experience excessive
      toxicity. Skeletally-mature subjects with recurrent or refractory SHH medulloblastoma will be
      eligible as soon the surgical study is initiated and will receive drug at 1000mg BID or its
      BSA adjusted equivalent depending upon age and BSA. Skeletally-immature subjects will only be
      eligible to enroll on the surgical trial once the MTD is defined in the Phase 1 component and
      will receive drug at the established MTD for this cohort.

      After completion of study treatment, patients are followed up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I - Skeletally-immatureExperimentalSkeletally-immature children with refractory or recurrent medulloblastoma of the SHH group
  • CX 4945
Phase II - Skeletally-matureExperimentalSkeletally-mature subjects with refractory or recurrent medulloblastoma of the SHH group
  • CX 4945
SurgicalExperimentalSubjects who are eligible for the Phase I or Phase II arm of the trial and are candidates for surgery, may be enrolled in the surgical arm prior to initiation of the Phase I or Phase II treatment.
  • CX 4945

Eligibility Criteria

        A. Screening Criteria:

        Subject must have a diagnosis of medulloblastoma that is recurrent or refractory and must
        have adequate tissue for SHH subgrouping.

        B. Inclusion Criteria:

          1. Phase I Skeletally-immature:

             a. Patient must be skeletally-immature at the time of study enrollment, defined as
             females with a bone age < 14 years and males with a bone age < 16 years. Patient must
             be ≥3 and ≤18 years of age and BSA must meet protocol restrictions.

          2. Phase II Skeletally-mature:

               1. Patients must be skeletally-mature, defined as females with a bone age ≥14 years
                  and males with a bone age ≥ 16 years OR have a chronological age >18 years.

               2. Must have bi-dimensionally measurable disease

          3. Surgical Study:

               1. Surgical resection must be clinically indicated.

               2. Must be ≥3 years.

               3. Must be amenable to receiving CX-4945 for 5-7 days prior to surgery

          4. All Phases:

               1. Must have a diagnosis of SHH medulloblastoma that is recurrent or progressive
                  which was confirmed histologically and subgrouping was completed using a CLIA
                  certified methylation based test.

               2. Prior Therapy

                    -  Must have received prior therapy which included radiation therapy and
                       recovered from acute treatment related toxicities.

                    -  Must have received the last dose of myelosuppressive therapy at least 21
                       days prior to enrollment and at least 42 days if nitrosourea.

                    -  Must have received the last dose of another investigational or biologic
                       agent ≥7 days prior. For agents known to have adverse events occurring
                       beyond 7 days, the period must be extended to accommodate the longer
                       interval. For monoclonal antibodies with prolonged half-lives, at least 3
                       half-lives must have elapsed.

                    -  Must have received last fraction of craniospinal or total body irradiation
                       or radiation to ≥50% of the pelvis >3 months prior to enrollment. Last
                       fraction of focal irradiation must be >4 weeks prior to enrollment.

                    -  Must be ≥ 6 months since allogeneic stem cell transplant with no evidence of
                       acute graft vs. host disease.

                    -  Must be ≥3 months since autologous stem cell transplant.

               3. Must be off all colony-forming growth factors at least 1 week prior to
                  enrollment. Must be off 2 weeks if the subject received a long-acting
                  formulation.

               4. If neurological deficits are present, must have been stable for a minimum of 1
                  week prior to enrollment.

                  • Patients with seizure disorders may be enrolled if seizures are well
                  controlled.

               5. Must have a Karnofsky/Lansky Performance status ≥50%

               6. Must have adequate organ and marrow function

               7. Subjects receiving dexamethasone must be on a stable or decreasing dose for at
                  least 1 week prior to enrollment.

               8. Female patients of childbearing potential must have a negative pregnancy test.

               9. Patients of child-bearing or child fathering potential must be willing to use
                  medically acceptable form of birth control while treated on this study and for 3
                  months after drug cessation.

              10. Parent or legal guardian must be able to understand and willing to sign the
                  written informed consent.

        C. Exclusion Criteria:

        1. All Phases

          1. Nursing mothers due to an unknown but potential risk for adverse events in nursing
             infants.

          2. Patients with a history of any other malignancy with the exception of patients with a
             secondary brain tumor if the patient's prior malignancy has been in remission for at
             least 5 years from the end of treatment.

          3. Patients with any of the following gastrointestinal disorders - difficulty swallowing
             or active malabsorption, uncontrolled diarrhea, gastritis, ulcerative colitis, Crohn's
             disease or hemorrhagic coloproctitis, history of gastric or small bowel surgery
             involving any extent of gastric or small bowel resection.

          4. Patients with any clinically significant unrelated systemic illness that would
             compromise the patient's ability to tolerate therapy, put them at additional risk for
             toxicity or interfere with the study procedures or results.

          5. Corrected QT (QTc) interval is >480ms

          6. Patients who are receiving other anti-cancer or investigational drug therapy

          7. Patients who are on warfarin or statins.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Maximum tolerated dose of CX-4945
Time Frame:4 weeks
Safety Issue:
Description:Defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic.

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:Up to 3 years from enrollment
Safety Issue:
Description:Interval of time between the date of initiation of protocol treatment and minimum date of documentation of PD, second malignancy, death due to any cause or date of last follow-up.
Measure:Objective response rate in the skeletally-immature cohort
Time Frame:Up to 2 years from enrollment
Safety Issue:
Description:Percentage of patients who achieve objective response in the skeletally-immature cohort
Measure:Plasma pharmacokinetics of CX-4945 in skeletally-mature subjects
Time Frame:4 weeks
Safety Issue:
Description:To report the plasma drug concentration of CX-4945 in skeletally-mature subjects
Measure:Relative frequency of genomic alterations in archival tissue
Time Frame:At time of enrollment
Safety Issue:
Description:Percentage of various genomic alterations will be reported
Measure:Surgical study: Reduction in CK2-mediated signaling in tumor.
Time Frame:4 weeks
Safety Issue:
Description:Change in CK2 activity in tumor tissue from patients on the surgical are at baseline and after treatment.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pediatric Brain Tumor Consortium

Trial Keywords

  • Medulloblastoma
  • Sonic Hedgehog (SHH) positive

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