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

Study Overview
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Brief Summary
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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
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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.

Official Title
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PBTC-053: A Pediatric Brain Tumor Consortium Phase I/ II and Surgical Study of CX-4945 in Patients With Recurrent SHH Medulloblastoma

Conditions
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Medulloblastoma, Childhood

Intervention / Treatment
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* Drug: CX 4945


Participation Criteria
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Eligibility Criteria
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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: 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. Phase II Skeletally-mature: 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. Must have bi-dimensionally measurable disease Surgical Study: Surgical resection must be clinically indicated. Must be ≥3 years. Must be amenable to receiving CX-4945 for 5-7 days prior to surgery All Phases: 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. 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. 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 controlled. 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. C. Exclusion Criteria: 1. All Phases 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. Corrected QT (QTc) interval is >480ms Patients who are receiving other anti-cancer or investigational drug therapy Patients who are on warfarin or statins.

Ages Eligible for Study
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Minimum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - Skeletally-immature<br>Skeletally-immature children with refractory or recurrent medulloblastoma of the SHH group | Drug: CX 4945<br>* CX-4945 is supplied as 200 mg capsules delivered orally as a formulated API<br>* Other names: Silmitasertib sodium;|
| Experimental: Phase II - Skeletally-mature<br>Skeletally-mature subjects with refractory or recurrent medulloblastoma of the SHH group | Drug: CX 4945<br>* CX-4945 is supplied as 200 mg capsules delivered orally as a formulated API<br>* Other names: Silmitasertib sodium;|
| Experimental: Surgical<br>Subjects 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. | Drug: CX 4945<br>* CX-4945 is supplied as 200 mg capsules delivered orally as a formulated API<br>* Other names: Silmitasertib sodium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum tolerated dose of CX-4945 | 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. | 4 weeks | 
| Phase I: Plasma pharmacokinetics of CX-4945 in skeletally-immature children | To report the plasma drug concentration of CX-4945 on this schedule in skeletally-immature children | 4 weeks | 
| Surgical Study: Intratumoral PK concentrations | Average tumor CX-4945 concentrations. | Prior to starting CX-4945 (Day -5 or -7), prior to dose on Day -3, prior to dose on Day -1, day of surgery and during surgery at the time of tissue collection | 
| Phase II: Sustained objective response rate (PR-CR) rate in the skeletally mature cohort | Percentage of patients who achieve sustained objective response. | Up to 2 years from enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | 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. | Up to 3 years from enrollment | 
| Objective response rate in the skeletally-immature cohort | Percentage of patients who achieve objective response in the skeletally-immature cohort | Up to 2 years from enrollment | 
| Plasma pharmacokinetics of CX-4945 in skeletally-mature subjects | To report the plasma drug concentration of CX-4945 in skeletally-mature subjects | 4 weeks | 
| Relative frequency of genomic alterations in archival tissue | Percentage of various genomic alterations will be reported | At time of enrollment | 
| Surgical study: Reduction in CK2-mediated signaling in tumor. | Change in CK2 activity in tumor tissue from patients on the surgical are at baseline and after treatment. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medulloblastoma, Sonic Hedgehog (SHH) positive