Testing CX-4945 for recurrent medulloblastoma in children

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

This study is testing a new oral drug called CX-4945 to see if it can safely help children with recurrent medulloblastoma, a type of brain cancer.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 66 (estimated)
• Ages: 3 Years and up
• Sex: All
• Sponsor: Pediatric Brain Tumor Consortium (Research network)
• Drugs / interventions: radiation
• Locations: 12 sites (Los Angeles, California and 11 other locations)
• Trial ID: NCT03904862 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the safety and tolerability of CX-4945, a drug administered orally, in children with recurrent Sonic Hedgehog (SHH) medulloblastoma. The study is divided into Phase I and Phase II, focusing on determining the maximum tolerated dose, assessing toxicity profiles, and characterizing pharmacokinetics. Additionally, it aims to document preliminary antitumor activity and explore genomic correlations with treatment response. The trial includes surgical components to analyze drug concentrations in tumor tissues.

Who should consider this trial

Good fit: Ideal candidates are skeletally-immature children diagnosed with recurrent SHH medulloblastoma who have failed standard therapies.

Not a fit: Patients with non-recurrent medulloblastoma or those who have not undergone prior standard therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for children suffering from recurrent medulloblastoma.

How similar studies have performed: While this approach is novel in the context of recurrent SHH medulloblastoma, similar studies targeting other cancers have shown promising results.

Eligibility criteria

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.

Where this trial is running

Los Angeles, California and 11 other locations

• Children's Hospital of Los Angeles — Los Angeles, California, United States (Recruiting)
• Stanford University and Lucile Packard Children's Hospital — Palo Alto, California, United States (Recruiting)
• Children's National Medical Center — Washington, District of Columbia, United States (Recruiting)
• University of Florida — Gainesville, Florida, United States (Recruiting)
• Children's Healthcare of Atlanta — Atlanta, Georgia, United States (Recruiting)
• Ann & Robert H. Lurie Children's Hospital of Chicago — Chicago, Illinois, United States (Recruiting)
• Memorial Sloan-Kettering Cancer Center — New York, New York, United States (Recruiting)
• Cincinnati Children's Hospital Medical Center — Cincinnati, Ohio, United States (Recruiting)
• Nationwide Children's Hospital — Columbus, Ohio, United States (Recruiting)
• Children's Hospital of Pittsburgh of UPMC — Pittsburgh, Pennsylvania, United States (Recruiting)
• St. Jude Children Research Hospital — Memphis, Tennessee, United States (Recruiting)
• Baylor College of Medicine — Houston, Texas, United States (Recruiting)

Study contacts

• Study coordinator: Vanetria Stokes, MS

Conditions Medulloblastoma, Childhood; Medulloblastoma Recurrent; Medulloblastoma; Sonic Hedgehog positive