CX-4945 for Medulloblastoma

Recruiting at12 trial locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Pediatric Brain Tumor Consortium

Must not be taking: Warfarin, Statins

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

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests an oral drug called CX-4945 for patients with a recurring type of brain tumor. The drug aims to block a protein that helps cancer cells grow. The study will determine the best dose and check for side effects. CX-4945 has shown promising results in other types of cancer and may be developed as a new therapy.

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.

How does the drug CX-4945 differ from other treatments for medulloblastoma?

CX-4945 is unique because it targets specific molecular pathways involved in medulloblastoma, potentially offering a more tailored approach compared to traditional treatments like surgery, radiation, and chemotherapy, which can have significant side effects. This drug may provide a new option for targeting the disease biology more precisely. ^{1 2 3 4 5}

Research Team

Ralph Salloum, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• CX-4945 (Protein Kinase Inhibitor)

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.

Participant Groups

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+

Dr. James R. Downing

St. Jude Children's Research Hospital

Chief Executive Officer since 2014

MD from University of Michigan Medical School

Dr. Ellis J. Neufeld

St. Jude Children's Research Hospital

Chief Medical Officer since 2017

MD, PhD from Harvard Medical School

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Medulloblastoma. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Principles of tumorigenesis and emerging molecular drivers of SHH-activated medulloblastomas. [2020]

3. China pubmed.ncbi.nlm.nih.gov

[Survival of children with recurrent medulloblastoma undergoing sequential therapy: an analysis of 101 cases]. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Development of Randomized Trials in Adults with Medulloblastoma-The Example of EORTC 1634-BTG/NOA-23. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma. [2023]