Status and phase
Conditions
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About
This research study involves a combination of three drugs given together as a possible treatment for malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, epithelioid sarcoma, chordoma or other tumors that are deficient in one of two possible proteins, either INI-1 (SMARCB1) or SMARCA4.
The names of the study drugs involved in this study are:
Full description
This research study involves a combination of three drugs given together as a possible treatment for these types of cancers. One drug is small molecule inhibitor targeting EZH2 (tazemetostat) and two are immunotherapeutic checkpoint inhibitors (nivolumab and ipilimumab). This is a Phase I/II clinical trial. Phase I clinical trials test the safety of an investigational drug, or combination of drugs, and tries to define the appropriate dose of the investigational drugs to use for further studies. Phase II clinical trials test the safety and effectiveness of an investigational drug, or drug combination, to learn whether the drug or drug combination works in treating a specific disease. "Investigational" means that the drug combination is being studied.
This trial is studying the combination of tazemetostat, nivolumab, and ipilimumab in two parts:
The research study procedures include screening for eligibility study treatment, evaluation and follow-up visits. Participants will be asked to provide blood samples and undergo procedures that might be different from a regular medical examination. There are additional research samples that participants will be asked to consent for their collection.
Participants will receive study treatment for up to 2 years, as long as there is benefit or there are no serious side effects. Participants will be followed for approximately 2 years after stopping treatment.
It is expected that about 49 people will take part in this research study.
The U.S. Food and Drug Administration (FDA) has not approved this combination of three drugs for this specific disease. However, tazemetostat has been approved for use in epithelioid sarcoma (an INI1-deficient tumor), and the combination of nivolumab and ipilimumab has also been approved for other uses. Separately, tazemetostat and the combination of nivolumab and ipilimumab have also been tested in children and the safest doses of each drug (and the combination for nivolumab and ipilimumab) have been determined.
Bristol-Myers Squibb and Epizyme, two pharmaceutical companies, are supporting this study by providing the study drugs. Dana-Farber Cancer Institute is also supporting this study by providing funding.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Diagnosis: Histologically confirmed tumors at diagnosis or at relapse (as applicable):
Stratum A
Stratum B
All subjects must have had tumor assessment at original diagnosis or relapse showing either of the following: Loss of INI1 confirmed by immunohistochemistry (IHC) OR molecular confirmation of tumor bi-allelic SMARCB1 (INI1) loss or mutation when INI1 IHC is equivocal or unavailable
Loss of SMARCA4 confirmed by IHC OR molecular confirmation of tumor SMARCA4 loss or mutation (with PI approval) Reports confirming these findings (including tumor sequencing if available) will be reviewed by the Sponsor-Investigator, PI or designee for approval of eligibility prior to enrollment.
Treatment status: All subjects must have completed planned upfront treatment for their disease for strata A1 or B1. Subjects need not have relapsed or have refractory disease to be eligible for this protocol.
Disease Status: For subjects under consideration for strata A1 or B1, subjects must have evaluable disease Note: Leptomeningeal lesions/disease are allowed as evaluable disease.
For relapsed/refractory subjects under consideration for strata A2 or B2, subjects must have measurable disease as defined by RANO for stratum A2 or RECIST v1.1 for stratum B2. See Section 11.
Note: the following do not qualify as measurable disease:
For subjects under consideration for strata A3 or B3, subjects must have no evidence of evaluable or measurable disease by exam or imaging.
Pre-recurrent subjects to be enrolled in strata A1, B1, A3, or B3 must be enrolled within 8 weeks of completion of upfront therapy
Age ≥ 6 months and ≤ 21years of age
Karnofsky performance status ≥ 50% for subjects ≥16 years of age and Lansky performance status ≥ 50% for subjects <16 years of age (see Appendix A). Note: Neurologic deficits in subjects with CNS tumors must have been stable for at least 7 days prior to study enrollment. Subjects 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.
Life expectancy of greater than 2 months.
Prior Therapy: Subjects must have fully recovered from the acute toxic effects of all prior anti-cancer therapy. Subjects must meet the following minimum washout periods prior to first day of study treatment:
Radiotherapy
Subjects must have adequate organ function as defined below:
Hepatic Function
Renal Function: A serum creatinine based on age/gender as follows: Maximum Serum Creatinine (mg/dL)
Adequate Pulmonary Function defined as: No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficient and a pulse oximetry > 92% while breathing room air.
-- Adequate Neurologic Function defined as: Subjects with seizure disorder may be enrolled if on anticonvulsants and well controlled. Nervous system disorders (CTCAE v5.0) resulting from prior therapy must be ≤ Grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible.
Negative B-HCG pregnancy test (urine or serum) in females of childbearing potential.
Women of childbearing potential (WOCBP) receiving the TAZNI combination agree to adhere to contraception for a period of 5 months after the last dose of either tazemetostat, nivolumab, or ipilimumab
Men receiving the TAZNI combination and who are sexually active with WOCBP will agree to adhere to barrier contraception for a period of 3 months after the last dose of either tazemetostat, nivolumab or ipilimumab.
Ability to understand and/or the willingness of the subject (or parent or legally authorized representative, if minor) to provide informed consent, documented using an institutionally approved informed consent procedure.
Exclusion criteria
Primary purpose
Allocation
Interventional model
Masking
49 participants in 8 patient groups
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Central trial contact
Susan Chi, MD
Data sourced from clinicaltrials.gov
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