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

  • STATUS
    Recruiting
  • End date
    Jun 2, 2028
  • participants needed
    60
  • sponsor
    Pediatric Brain Tumor Consortium
Updated on 7 October 2022

Summary

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

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.

Details
Condition Medulloblastoma, Childhood
Treatment CX 4945
Clinical Study IdentifierNCT03904862
SponsorPediatric Brain Tumor Consortium
Last Modified on7 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Phase I Skeletally-immature
a. Patient must be skeletally-immature at the time of study enrollment, defined as
Phase II Skeletally-mature
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
Must have bi-dimensionally measurable disease
Surgical Study
Patients must be skeletally-mature, defined as females with a bone age ≥14 years
Surgical resection must be clinically indicated
and males with a bone age ≥ 16 years OR have a chronological age >18 years
Must be amenable to receiving CX-4945 for 5-7 days prior to surgery
All Phases
Must be ≥3 years
Prior Therapy
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
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
controlled
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
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
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
Must have a Karnofsky/Lansky Performance status ≥50%
Must have adequate organ and marrow function
Subjects receiving dexamethasone must be on a stable or decreasing dose for at
least 1 week prior to enrollment
Female patients of childbearing potential must have a negative pregnancy test
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
Parent or legal guardian must be able to understand and willing to sign the
written informed consent

Exclusion Criteria

All Phases
Corrected QT (QTc) interval is >480ms
Patients who are receiving other anti-cancer or investigational drug therapy
Patients who are on warfarin or statins
Nursing mothers due to an unknown but potential risk for adverse events in nursing
infants
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
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
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
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