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

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and recommend a Phase II dose 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 associated with CX-4945 in children with recurrent SHH (Sonic hedgehog) medulloblastoma (Phase I) III. To characterize the pharmacokinetics of CX-4945 administered on this schedule in skeletally-immature children with recurrent SHH 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.

• CX 4945 (Drug), also known as Silmitasertib sodium: CX-4945 is supplied as 200 mg capsules delivered orally as a formulated API

Primary outcomes

• Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) [up to 4 weeks for each dosing cohort]: DLT is any event occurring during the dose-finding period (Course 1) that is at least possibly related to CX-4945, regardless of expectedness. DLTs include: (1) any CX-4945-related AE leading to dose reduction, permanent treatment discontinuation, or treatment delay >14 days (dose modifications per Sections 7.1 and 7.2); (2) non-hematologic toxicity: any Grade 4 event; any Grade 3 event except controllable Grade 3 nausea/vomiting, supportive care-responsive Grade 3 diarrhea, reversible Grade 3 AST/ALT returning to eligibility levels within 7 days of treatment interruption without recurrence on rechallenge, Grade 3 fever, Grade 3 infection, or enteral supplementation-responsive Grade 3 electrolyte abnormalities; and any non-hematologic toxicity persisting ≥14 days that is medically significant or intolerable enough to require treatment interruption; (3) hematologic toxicity: Grade 3/4 thrombocytopenia or Grade 4 neutropenia.
• Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D) of CX-4945 in Skeletally Immature Patients [4 weeks]: The rolling-6 design was used to estimate the MTD in the Phase I group. The MTD was 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.
• Intratumoral PK Concentrations in Surgical Cohort Participants [During surgery at the time of tissue collection]: Average tumor CX-4945 concentrations in surgical patients
• Sustained Objective Response (PR-CR) Rate in Skeletally-mature Patients [Up to 2 years from enrollment]: A sustained objective responder is defined as a patient who achieves a confirmed partial response or complete response, which also must be sustained for at least 8 weeks with central radiographic confirmation. Response rates will be calculated as the percent of evaluable patients who are responders. Tumor response criteria are determined by changes in size, measured as the longest tumor dimension and its perpendicular. FLAIR, T2 or post contrast T1 weighted images may be used - whichever gives the best estimate of tumor size.
• Pharmacokinetic (PK) Parameters of CX4945, Area Under the Curve (AUC), in Skeletally Immature Patients [Day 1 and day 28 of the course 1.]: The mean of the AUC evaluated at day 1 and day 28 of course 1 in skeletally immature patients who had plasma sample available.

Secondary outcomes

• Progression Free-Survival (PFS) [up to 24 months from enrollment]: The Kaplan-Meier method will be used to estimate the median survival time of PFS. The PFS is defined as the time between treatment initiation until progression or death for any reason for patients who experience an event and last follow-up for patients who are event-free at the time of analysis.
• Sustained Objective Response (PR-CR) Rate in Skeletally-immature Patients [Up to 2 years from enrollment]: A sustained objective responder is defined as a patient who achieves a confirmed partial response or complete response, which also must be sustained for at least 8 weeks with central radiographic confirmation. Response rates will be calculated as the percent of evaluable patients who are responders. Tumor response criteria are determined by changes in size, measured as the longest tumor dimension and its perpendicular. FLAIR, T2 or post contrast T1 weighted images may be used - whichever gives the best estimate of tumor size.
• Pharmacokinetic (PK) Parameters of CX4945, Area Under the Curve (AUC), in Skeletally Mature Patients [Day 1 and day 28 of the course 1.]: The mean of the AUC evaluated on day 1 and day 28 of course 1 in skeletally mature patients with a plasma sample available.
• Correlation Between Response to Treatment and the Presence of Specific Genomic Alterations [At time of enrollment]: Estimated correlation coefficient between antitumor response and presence of genomic alterations.
• Reduction in CK2-mediated Signaling in Tumor for Surgical Participants [4 weeks]: Change in CK2 activity in tumor tissue from patients on the surgical are at baseline and after treatment.

Sex: All, ages: 3 Years to any

Screening Criteria:

1. Tumor

   a. Patient must have a diagnosis of medulloblastoma that is recurrent or progressive. All tumors must have histologic verification either at the time of diagnosis or recurrence.
2. Adequate Pre-trial Tumor Tissue a. Patient must have adequate pre-trial tumor material available for subgrouping.
3. Prior Therapy

   a. Patient must have received and failed standard therapy for medulloblastoma.
4. Screening Consent a. Participant is willing to sign a screening consent. The screening consent is for subgroup testing for all participants and for bone age determination in subjects ≤ 18 years. The screening consent is to be obtained according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines.

Inclusion Criteria:

1. Phase I Skeletally-immature:

   1. 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.
   2. Patients who participate in the expansion cohort must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions (Section 12.2.2). Patients with measurable extraneural disease only are also eligible.
   3. Patient must be ≥ 3 and ≤ 18 years of age at the time of enrollment.
   4. Patients enrolled on the Phase I study must have a BSA as noted below:

   Dose Level 0 (400 mg/m2 BID): Minimum - 0.84m2; Maximum - 2.25m2 Dose Level 1 (600 mg/m2 BID): Minimum - 0.60m2; Maximum - 2.00m2 Dose Level 2 (800 mg/m2 BID): Minimum - 0.63m2; Maximum - 2.00m2
2. Phase II Skeletally-mature:

   a. 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.

   b. Patients must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions. Patients with measurable extraneural disease only are also eligible.
3. Surgical Study:

   1. Surgical resection must be clinically indicated.
   2. Must be ≥3 years at time of enrollment.
   3. Must be amenable to receiving CX-4945 for 5-7 days prior to surgery
4. All Phases:

   1. Patient must have a diagnosis of SHH medulloblastoma that is recurrent or progressive, confirmed histologically and by CLIA-certified methylation-based subgroup testing at Cincinnati Children's Hospital Medical Center (CCHMC), Memorial Sloan Kettering Cancer Center (MSKCC), National Cancer Institute (NCI), or Nationwide Children's Hospital (NCH). Results from prior testing at these designated sites using the same approaches described for this study will be accepted.
   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 >12 weeks prior to enrollment. Last fraction of focal irradiation must be >4 weeks prior to enrollment.

      • Must be ≥ 24 weeks since allogeneic stem cell transplant with no evidence of acute graft vs. host disease.

      • Must be ≥12 weeks 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.

Participant flow

Outcome results

• Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) (Primary), Count of participants, Participants: Phase I Dose Level 1: 600 mg/m^2 0; Phase I Dose Level 2: 800 mg/m^2 0; Phase II Dose Level 1: 600 mg/m^2 or 1000 mg 1
• Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D) of CX-4945 in Skeletally Immature Patients (Primary), Number, mg/m^2 twice a day: All Participants in Phase I NA
• Intratumoral PK Concentrations in Surgical Cohort Participants (Primary), Mean, ng/mL: Surgical Dose Level 1: 600 mg/m^2 or 1000 mg 92.5 (54 to 131)
• Progression Free-Survival (PFS) (Secondary), Number, Months: Phase I Dose Level 1: 600 mg/m^2 1.8 (0.9 to NA); Phase I Dose Level 2: 800 mg/m^2 1.8 (1.5 to NA); Phase II Dose Level 1 + Surgical Dose Level 1 1.8 (1.7 to 2.3)
• Sustained Objective Response (PR-CR) Rate in Skeletally-immature Patients (Secondary), Number, Percentage of evaluable participants
• Pharmacokinetic (PK) Parameters of CX4945, Area Under the Curve (AUC), in Skeletally Mature Patients (Secondary), Mean, h·ng/mL: Phase II Dose Level 1 + Surgical Dose Level 1 5962 +/- 5309
• Correlation Between Response to Treatment and the Presence of Specific Genomic Alterations (Secondary), Number, correlation coefficient
• Reduction in CK2-mediated Signaling in Tumor for Surgical Participants (Secondary), Mean, log2 fold change
• Sustained Objective Response (PR-CR) Rate in Skeletally-mature Patients (Primary), Number, percentage of evaluable participants: Phase II Dose Level 1 + Surgical Dose Level 1 0 (0 to 28.5)
• Pharmacokinetic (PK) Parameters of CX4945, Area Under the Curve (AUC), in Skeletally Immature Patients (Primary), Mean, h·ng/mL: Phase I Dose Level 1: 600 mg/m^2 10324 +/- 10546; Phase I Dose Level 2: 800 mg/m^2 9993 +/- 6518

Adverse events

Time frame: Up to 2 years after starting treatment

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The study was permanently closed to accrual on October 23, 2025 without completing the targeted accrual, due to the NCI discontinuing funding for PBTC.

• Study Protocol and Statistical Analysis Plan (PDF, 2024-10-10)

• Ralph Salloum, MD, Study chair, Dana-Farber Cancer Institute

NIH grants: UM1CA081457