Tazemetostat+Nivo/Ipi in INI1-Neg/SMARCA4-Def Tumors
TAZNI: A Phase I/II Combination Trial of Tazemetostat With Nivolumab and Ipilimumab for Children With INI1-Negative or SMARCA4-Deficient Tumors
1 other identifier
interventional
49
1 country
3
Brief Summary
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:
- Tazemetostat (TAZVERIK)
- Nivolumab (OPDIVO)
- Ipilimumab (YERVOY)
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Aug 2023
Longer than P75 for phase_1
3 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 2, 2022
CompletedFirst Posted
Study publicly available on registry
June 7, 2022
CompletedStudy Start
First participant enrolled
August 10, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
February 1, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
February 1, 2029
April 13, 2026
April 1, 2026
3.5 years
June 2, 2022
April 7, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Incidence of Grade 3 or Higher Treatment-Related Toxicity
All grade 3 or higher adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAE v5 as reported on case report forms will be counted. Incidence is the number of patients experiencing at least one treatment-related grade 3 or higher AE of any type during the time of observation.
AE to be collected continuously after the patient has provided informed consent through up to 30 days after last dose of study treatment up to 5.5 years
Maximal Tolerated Dose (MTD)
The MTD defined as the dose level associated with observed DLTs in \<33% of enrolled subjects. The DLT assessment will be restricted to the first cycle.
Treatment duration is a median of N cycles range (t1 - t2). Treatment continues until disease progression or unacceptable toxicity up to 5.5 years
Secondary Outcomes (4)
Recommended Pediatric Phase 2 Dose (RP2D)
Treatment duration is a median of N cycles range (t1 - t2). Treatment continues until disease progression or unacceptable toxicity up to 5.5 years
Overall Response Rate (ORR)
Disease is evaluated each cycle on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of N cycles range (t1 - t2) up to 5.5 years
Median Overall Survival (OS)
Up through 5.5 years
Median Progression-free survival (PFS)
Participants are followed for survival every 6 months, up to 3 years after treatment discontinuation
Study Arms (8)
Phase I a: DOSE ESCALATION (STRATUM A, ATRT and primary CNS malignant tumor, INI/SMARCA4-deficient)
EXPERIMENTALPart 1 will be two concurrent "rolling six" phase 1 studies starting at a different tazemetostat dose for each stratum), with one dose escalation and one dose de-escalation planned. All subjects will receive the same nivolumab and ipilimumab doses and dosing schedule
Phase I b: DOSE ESCALATION (STRATUM B, NON-ATRT, NON-CNS)
EXPERIMENTALPart 1 will be two concurrent "rolling six" phase 1 studies starting at a different tazemetostat dose for each stratum), with one dose escalation and one dose de-escalation planned. All subjects will receive the same nivolumab and ipilimumab doses and dosing schedule
EXP A1: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA A1)
EXPERIMENTALOnce the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status
EXP A2: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA A2)
EXPERIMENTALOnce the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status
EXP A3: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA A3)
EXPERIMENTALOnce the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status
EXP B1: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA B1)
EXPERIMENTALOnce the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status
EXP B2: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA B2)
EXPERIMENTALOnce the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status
EXP B3: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA B3)
EXPERIMENTALOnce the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status
Interventions
oral, twice daily, dosage per protocol
IV, dosage and schedule per protocol
IV, dosage and schedule per protocol
Eligibility Criteria
You may qualify if:
- Diagnosis: Histologically confirmed tumors at diagnosis or at relapse (as applicable):
- Stratum A
- Atypical Teratoid Rhabdoid Tumor (ATRT)
- Other INI1- or SMARCA4-deficient primary CNS malignant tumors (with PI approval)
- Stratum B
- Malignant rhabdoid tumor (MRT)
- Rhabdoid tumor of the kidney (RTK)
- Epithelioid sarcoma
- Chordoma (poorly differentiated or de-differentiated)
- Other INI1- or SMARCA4-deficient malignant tumors (with PI approval)
- 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.
- +44 more criteria
You may not qualify if:
- Concomitant Medications
- Subjects who are receiving any other investigational agents or other anti-cancer agents are not eligible.
- CYP3A4 Agents: Subjects who are currently receiving drugs that are strong or moderate inducers or inhibitors of CYP3A4 are not eligible. Such inducers or inhibitors of CYP3A4 are prohibited from 14 days prior to the first dose of tazemetostat to the end of the study. See Appendix C for a list of agents. Note:Dexamethasone for CNS tumors or metastases, on a stable or decreasing dose, is allowed up to 0.12mg/kg/day prednisone equivalents.
- Subjects with a known history of HIV, hepatitis B, and/or hepatitis C (testing not required as part of screening).
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or any other concurrent disease which in the judgment of the Investigator would make the subject inappropriate for enrollment on this study.
- Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
- Has active autoimmune disease that has required systemic treatment in the past 12 months, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy are exceptions. Intermittent use of bronchodilators or local steroid injections are not excluded. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Autoimmune diagnoses not listed must be approved by the Principal Investigator.
- On screening CBC differential, subjects must not have any significant morphologic abnormalities concerning for MPN/MDS or ALL.
- Subjects must not have any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS) or prior history of lymphoblastic lymphoma (LBL) or leukemia (ALL).
- Subjects who have received prior solid organ transplantation are not eligible.
- Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as there is yet no available information regarding human fetal or teratogenic toxicities.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA4 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. OX40, CD137).
- Subjects who have received live / attenuated vaccine within 30 days of first dose of study treatment.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to tazemetostat or Orasweet.
- Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Susan Chi, MDlead
- Bristol-Myers Squibbcollaborator
- Epizyme, Inc.collaborator
Study Sites (3)
Boston Children's Hospital
Boston, Massachusetts, 02115, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215, United States
Texas Children's Hospital
Houston, Texas, 77030, United States
Related Publications (1)
Roden AC. Molecularly Defined Thoracic Neoplasms. Adv Anat Pathol. 2024 Sep 1;31(5):303-317. doi: 10.1097/PAP.0000000000000439. Epub 2024 Mar 19.
PMID: 38501690DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Susan Chi, MD
Dana-Farber Cancer Institute
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR INVESTIGATOR
- PI Title
- Sponsor Investigator
Study Record Dates
First Submitted
June 2, 2022
First Posted
June 7, 2022
Study Start
August 10, 2023
Primary Completion (Estimated)
February 1, 2027
Study Completion (Estimated)
February 1, 2029
Last Updated
April 13, 2026
Record last verified: 2026-04
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP
- Time Frame
- Data can be shared no earlier than 1 year following the date of publication
- Access Criteria
- Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.