CX-4945 for Medulloblastoma

No longer recruiting at 13 trial locations

Overseen By Nina Butingan, MBS

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Pediatric Brain Tumor Consortium

Must not be taking: Warfarin, Statins

Disqualifiers: Nursing mothers, Other malignancy, Gastrointestinal disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, CX-4945, for individuals with SHH medulloblastoma, a type of brain cancer. The trial aims to determine if CX-4945 can benefit those whose cancer has returned or resisted other treatments. Participants are divided into different groups: one for skeletally-immature children, another for skeletally-mature participants, and a surgical group for those requiring surgery. Ideal candidates for this trial have SHH medulloblastoma that has recurred or worsened despite previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as warfarin and statins, before participating. If you are on other anti-cancer or investigational drug therapies, you will also need to stop those before enrolling.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CX-4945, also known as silmitasertib sodium, is under evaluation for safety in treating medulloblastoma, a type of brain cancer. In earlier studies, patients took CX-4945 twice daily to assess tolerance. Initial results indicated that patients managed the treatment, although some experienced side effects.

The trial began with a small group of patients who had finished growing to ensure safety. This careful approach helps researchers identify any serious side effects early. Since the study remains in its early stages, not all side effects are known. However, being in these early phases means the treatment is still under safety evaluation in humans. Participants should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Unlike the standard treatments for medulloblastoma, which often include surgery, radiation, and chemotherapy, CX-4945 offers a novel approach by specifically targeting the SHH (Sonic Hedgehog) pathway, which is a common driver in this type of cancer. This pathway is crucial for the growth and survival of cancer cells in certain subtypes of medulloblastoma. Researchers are excited because CX-4945 acts as a protein kinase inhibitor, potentially stopping the cancer cells from multiplying and spreading. This targeted mechanism could lead to more effective treatments with fewer side effects compared to the traditional methods.

What evidence suggests that this trial's treatments could be effective for medulloblastoma?

Research has shown that CX-4945, also known as silmitasertib sodium, may help treat medulloblastoma, particularly in the Sonic Hedgehog (SHH) group. Studies have found that CX-4945 can reduce cancer cell numbers in lab tests using human medulloblastoma cells. Another study suggested that CX-4945 might be safer for patients because it targets specific parts of the cancer's growth process. Additionally, CX-4945 has received fast-track status for treating recurring SHH medulloblastoma, highlighting its potential importance and effectiveness. This trial will evaluate CX-4945 in different participant groups, including skeletally mature and skeletally immature subjects, as well as those eligible for surgery, indicating that CX-4945 could be a promising treatment option for patients with recurring SHH medulloblastoma. ^{1 2 6 7 8}

Who Is on the Research Team?

Ralph Salloum, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for patients with recurrent SHH medulloblastoma, a type of brain cancer. Participants must be skeletally mature or over 18 years old, have measurable disease, and have undergone prior treatments including radiation. They should not be nursing mothers or have other cancers (unless in remission for 5+ years), significant unrelated illnesses, certain gastrointestinal disorders, or an abnormal heart rhythm (QTc >480ms).

Inclusion Criteria

My medulloblastoma is recurring or worsening and was confirmed with specific tests.

I am an adult or a teen with mature bones and my disease can be measured in two ways.

I am under 18, my growth plates are not fully developed, and my body size fits the study requirements.

Exclusion Criteria

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Dose-escalation study to determine the maximum tolerated dose of CX-4945 in skeletally-immature children with recurrent SHH medulloblastoma

4 weeks

Continuous dosing

Surgical Study

Characterization of intratumoral pharmacokinetics and CK2-mediated signaling reduction in tumor tissue

4 weeks

Multiple visits for surgical assessment and tissue collection

Phase II Treatment

Establish safety and characterize toxicity of 1000mg BID continuous dosing of CX-4945 in skeletally-mature patients

Continuous

Continuous dosing

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• CX-4945

Trial Overview The trial is testing the safety and effects of CX-4945 (silmitasertib sodium) on patients with recurrent SHH medulloblastoma. It includes both Phase I and II stages as well as a surgical study where some participants may undergo surgery.

How Is the Trial Designed?

Group I: Surgical Experimental Treatment 1 Intervention

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.

Group II: Phase II - Skeletally-mature Experimental Treatment 1 Intervention

Skeletally-mature subjects with refractory or recurrent medulloblastoma of the SHH group

Group III: Phase I - Skeletally-immature Experimental Treatment 1 Intervention

Skeletally-immature children with refractory or recurrent medulloblastoma of the SHH group

Who Is Running the Clinical Trial?

Pediatric Brain Tumor Consortium

Lead Sponsor

Trials

38

Recruited

1,600+

American Lebanese Syrian Associated Charities (ALSAC)

Collaborator

Trials

9

Recruited

670+

Senhwa Biosciences, Inc.

Industry Sponsor

Trials

9

Recruited

530+

National Cancer Institute/NIH/DHHS (NCI)

Collaborator

Trials

2

Recruited

320+

American Lebanese Syrian Associated Charities

Collaborator

Trials

9

Recruited

670+

St. Jude Children's Research Hospital

Collaborator

Trials

451

Recruited

5,326,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

SHH-activated medulloblastomas (SHH-MB) are characterized by specific genetic mutations, particularly in the sonic hedgehog signaling pathway, with over 95% of cases containing at least one driver mutation, which significantly impacts prognosis and treatment strategies.

The presence of TP53 mutations is associated with poorer outcomes, especially in older children, while distinct genetic alterations in adult patients suggest the need for tailored therapies; however, current subgroup classifications do not reliably predict treatment responses, highlighting the necessity for improved clinical trial designs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Principles of tumorigenesis and emerging molecular drivers of SHH-activated medulloblastomas. Menyhárt, O., Győrffy, B.[2020]

The EORTC 1634-BTG/NOA-23 trial aims to improve treatment for post-pubertal medulloblastoma patients by comparing standard-dose versus reduced-dose craniospinal radiotherapy and adding the SMO inhibitor sonidegib to standard therapy, potentially reducing toxicity and enhancing efficacy.

This study will provide valuable long-term data on treatment side effects and quality of life, which is crucial for developing better treatment strategies for this rare brain cancer in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Randomized Trials in Adults with Medulloblastoma-The Example of EORTC 1634-BTG/NOA-23. Hau, P., Frappaz, D., Hovey, E., et al.[2021]

Medulloblastoma (MB) is a complex group of brain tumors with four distinct subgroups (WNT, SHH, Group 3, and Group 4), each linked to different genetic changes and patient outcomes, highlighting the need for personalized treatment approaches.

Current management of MB includes surgery, radiation, and chemotherapy, but future strategies may focus more on the biological characteristics of the tumors to improve patient outcomes through tailored therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medulloblastoma. Northcott, PA., Robinson, GW., Kratz, CP., et al.[2021]

In a study of 101 children with recurrent medulloblastoma, remission induction therapy achieved a response rate of 54%, but the median overall survival after recurrence was only 13 months, highlighting the challenges in treating this condition.

Reoperation after recurrence significantly improved survival outcomes, with children who underwent reoperation having a 61.1% lower risk of death compared to those who did not, suggesting that early surgical intervention may enhance survival in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Survival of children with recurrent medulloblastoma undergoing sequential therapy: an analysis of 101 cases]. Sun, YL., Liu, JJ., DU, SX., et al.[2021]

MYC-amplified medulloblastoma can be categorized into OLIG2-high and OLIG2-low tumors, with OLIG2-high tumors showing resistance to radiation and a higher likelihood of recurrence, while OLIG2-low tumors are more sensitive to radiation and less likely to relapse.

Targeting OLIG2 using CRISPR or the small molecule inhibitor CT-179, in combination with radiotherapy, effectively prevents recurrence in OLIG2-high tumors, suggesting that OLIG2 is both a biomarker and a promising therapeutic target for improving outcomes in high-risk medulloblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma. Xu, Z., Murad, N., Malawsky, D., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03904862

Testing the Safety and Tolerability of CX-4945 in Patients ... To document preliminary antitumor activity of CX-4945 in skeletally-immature children with recurrent SHH medulloblastoma (Phase I). II. To perform a genomic ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6800621/

Casein Kinase 2 inhibition sensitizes medulloblastoma to ... Together our findings indicate that CX-4945 can be an effective and safer treatment for MB patients. These findings provided the basis for the ...

3. pbtc.org pbtc.org/public/Summaries/PBTC-053/PBTC-053%20CX-4945%20v2.0%20Abstract%20for%20Health%20Care%20Professionals.pdf

SCHEMA We have previously shown that treating SHH MBs with CX-4945 results in a dose-dependent loss in tumor cell viability in multiple human MB cell lines. These ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7237968/

Current medulloblastoma subgroup specific clinical trials - PMC ... CX-4945 in Patients With Recurrent SHH Medulloblastoma, NCT03904862, 60, Only ... Children with WNT medulloblastoma have by far the most favorable outcomes of all ...

5. onclive.com onclive.com/view/silmitasertib-gets-fast-track-status-for-recurrent-sonic-hedgehog-driven-medulloblastoma

Silmitasertib Gets Fast Track Status for Recurrent Sonic ... Testing the safety and tolerability of CX-4945 in patients with recurrent medulloblastoma who may or may not have surgery. ClinicalTrials ...

6. cincinnatichildrens.org cincinnatichildrens.org/service/c/clinical-trials/studies/PBTC-053

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

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03904862/

Clinical Trial: NCT03904862 - Medulloblastoma 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 ...

8. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-00180

CX-4945 in Treating Patients with Recurrent SHH ... This phase I/II trial studies the best dose and side effects of CX-4945, and how well it works in treating patients with sonic hedgehog (SHH) medulloblastoma ...