A phase 1 study of modified measles virus for the treatment of children and young adults with recurrent medulloblastoma or recurrent atypical teratoid rhabdoid tumors (ATRT)
This is a Phase I, open-label, multicenter study for children and young adults with locally recurrent or disseminated reccurent medulloblastoma or atypical teratoid rhabdoid tumors (ATRT). This study is testing the safety and oncolytic activity of the attenuated modified measles virus (MV-NIS), which is injected into the tumor bed or into the subarachnoid space.
Rationale for Study
For children with recurrent medulloblastoma or ATRT, outcomes remains very poor. Preclinical studies have shown that treatment with modified, attenuated measles virus (MV-NIS) leads to prolonged survival in models of recurrent medulloblastoma and ATRT. Safety studies have proven that MV-NIS has an excellent safety profile and ongoing adult studies are currently testing MV NIS in adult glioblastoma, ovarian cancer, and multiple myeloma.
Patients are stratified at time of enrollment into two groups. Group A: Patients with locally recurrent medulloblastoma or ATRT will undergo surgery to remove the recurrent tumor and the MV-NIS virus will be injected directly into the tumor bed. Group B: Patients with recurrent disseminated medulloblastoma or ATRT will receive MV-NIS via lumbar puncture into the subarachnoid space.
Following the one-time MV-NIS injection, patients will be monitored for safety and toxicity and follow-up will continue for 24 months.
To determine the safety and recommended phase 2 dose of modified measles virus if administered into the tumor bed of patients with locally recurrent disease or into the subarachnoid space of patients with disseminated disease.
To preliminarily define the anti-tumor activity of MV-NIS in children with recurrent medulloblastoma or ATRT by analyzing the objective response rate or 6-month progression-free survival rate.
To determine the distribution of MV-NIS after local injection or after administration into the subarachnoid space with SPECT imaging.
1. For stratum A, patients must have local recurrent disease (defined as negative spine MRI and negative cytology within 21 days prior to study registration) and undergo resection of local recurrence as part of their standard of care. Children must have undergone what is considered the standard of care as upfront therapy including either surgery followed by high dose chemotherapy with stem cell rescue or multi-modality therapy of surgery, radiation and chemotherapy.
For stratum B, patients must have disseminated recurrent disease (defined as multifocal disease, positive spine MRI including leptomeningeal disease and/or positive cytology within 21 days prior to study registration) and have adequate CSF flow based on spine MRI with no evidence of bulky disease or if bulky disease is present based on a CSF flow study per institutional guidelines. Children must have undergone what is considered the standard of care as upfront therapy including either surgery followed by high-dose chemotherapy with stem cell rescue or multi-modality therapy of surgery, radiation and chemotherapy.
2. Prior therapy: Patients must have failed at least one prior therapy prior to study registration (such as surgery followed by high-dose chemotherapy with stem cell rescue or multimodal treatment with surgery, radiation and chemotherapy). Patients must have fully recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
Myelosuppressive chemotherapy: Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three weeks prior to study registration or at least six weeks prior if chemotherapy was a nitrosourea.
Biologic agents: Patients must have recovered from any toxicity potentially related to the agent and received their last dose of the biologic agent ≥7 days prior to study registration.
- For agents that have known adverse events occuring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval should be discussed with the study chair.
- For agents that have a pro-longed half-life, the appropriate interval since last treatment should be discussed with the study chair prior to registration.
Monoclonal antibody treatment: At least three half-lives must have elapsed prior to registration. Such patients should be discussed with the study chair prior to registration. For bevacizumab, patients must have received last dose ≥ 32 days prior to study registration.
Radiation therapy: Patients must have had their last fraction of local irradiation to primary tumor ≥ 12 weeks prior to registration. Patients must have had their last fraction of craniospinal irradiation or total body irradiation ≥12 weeks prior to registration.
3. Age: ≥12 months to ≤39 years
4. Karnofsky performance status ≥50 for patients ≥16 years of age and Lansky ≥50 for patients <16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. Patients with pre-existing neurological deficits need to be stable prior to surgery or lumbar puncture as determined by the investigator.
5. Anti-measles virus immunity as demonstrated by IgG antimeasles antibody per insitutional guidelines (within 21 days prior to registration).
6. Adequate bone marrow defined as:
- Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 AND
- Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
7. Adequate Renal function defined as:
- Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR a serum creatinine within normal limits based on age and gender as follows:
- Age 1 to 2 years: 0.6 (male); 0.6 (female)
- Age 2 to <6 years: 0.8 (male); 0.8 (female)
- Age 6 to <10 years: 1 (male); 1 (female)
- Age 10 to <13 years: 1.2 (male); 1.2 (female)
- Age 13 to <16 years: 1.5 (male); 1.4 (female)
- Age ≥ 16 years: 1.7 (male); 1.4 (female)
8. Adequate liver function defined as:
- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age AND
- SGPT (ALT) ≤ 110 U/L AND
- Serum albumin ≥ 2 g/dL
9. The effects of MV-NIS on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception: hormonal or barrier method of birth control; abstinence prior to study entry and for the duration of study participation, and 4 months after completion of MV-NIS administration. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
10. Ability to understand and the willingness to sign a writeen informed consent document.
1. Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
2. Patients who are receiving any other investigational agents
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to measles virus vaccination
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
5. Female patients of childbearing potential must not be pregnant or breast-feeding.
6. Female patients of childbearing potential must have a negative serum or urine pregnancy test (within 7 days prior to study registration)
7. HIV-positive patients
8. Patients with very low CD4 counts (<200/μL or 14% of total lymphocyte count)
9. Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy
10. Exposure to household contact with known immunodeficiency
11. Allergy to measles vaccine or history of severe reaction to prior measles vaccination
12. History of chronic hepatitis B or C infection
13. History of organ transplantation
14. Patients with evidence of extraneural disease
15. Patients on chronic steroid use or other immunosuppressive agents
How to Enroll
If you believe your child or patient is eligible for this trial, contact the closest participating site for more information or contact us at email@example.com.