What side effects are associated with this type of intervention?

Common treatments for primary CNS malignant tumors, such as EZH2 inhibitors (e.g., Tazemetostat), PD-1 inhibitors (e.g., Nivolumab), and CTLA-4 inhibitors (e.g., Ipilimumab), have several known side effects. EZH2 inhibitors can cause fatigue, nausea, and thrombocytopenia. PD-1 inhibitors often lead to immune-related adverse events such as colitis, hepatitis, pneumonitis, and endocrinopathies. CTLA-4 inhibitors are associated with a higher incidence of immune-related side effects, including severe colitis, dermatitis, and endocrinopathies. General side effects of treatments for CNS tumors can also include neurotoxicity, cognitive changes, and increased risk of infections.

What prior FDA approvals exist?

The FDA has approved several treatments for primary CNS malignant tumors, though specific approvals for drugs targeting EZH2, PD-1, and CTLA-4 in this context are limited. Temozolomide, an alkylating agent, is commonly used for glioblastoma. Nivolumab (PD-1 inhibitor) and Ipilimumab (CTLA-4 inhibitor) have shown promise in various cancers, including CNS tumors, but their use is more established in melanoma and lung cancer. Tazemetostat, an EZH2 inhibitor, is approved for epithelioid sarcoma and follicular lymphoma, with ongoing research in CNS tumors. These approvals highlight the evolving landscape of targeted therapies in oncology.

What other types of research exist?

Promising novel alternatives for primary CNS malignant tumors include: 1) Lorlatinib, which has shown brain penetration and efficacy in ALK-positive NSCLC with CNS metastases. 2) Alectinib, effective against systemic disease and brain metastases in ALK-rearranged NSCLC. 3) Osimertinib, which improves overall survival in EGFR-mutated NSCLC with leptomeningeal metastases. These therapies target specific genetic mutations and have demonstrated efficacy in CNS involvement, making them potential alternatives for primary CNS malignant tumors.

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Checkpoint Inhibitor

Tazemetostat + Immunotherapy for Cancer

Q: What is the mechanism of action of this treatment?

The most common treatments for Primary CNS Malignant Tumors include targeted therapies and immunotherapies. Tazemetostat is an EZH2 inhibitor that works by blocking the EZH2 protein, which is involved in gene expression and tumor growth. Nivolumab is a PD-1 inhibitor that prevents cancer cells from evading the immune system by blocking the PD-1 pathway, thereby enhancing the body's immune response against the tumor. Ipilimumab is a CTLA-4 inhibitor that also boosts the immune response by blocking the CTLA-4 protein, which normally downregulates immune activity. These mechanisms are significant for patients as they offer targeted approaches to disrupt tumor growth and enhance immune-mediated tumor destruction, potentially leading to better treatment outcomes.

Phase 1 & 2

Recruiting

Research Sponsored by Susan Chi

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Karnofsky performance status ≥ 50% for subjects ≥16 years of age and Lansky performance status ≥ 50% for subjects <16 years of age

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)

Must not have

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

Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis

Timeline

Screening 3 weeks

Treatment Varies

Follow Up treatment duration is a median of n cycles range (t1 - t2). treatment continues until disease progression or unacceptable toxicity up to 5.5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a combination of three drugs to treat children with specific hard-to-treat cancers. The drugs work by blocking cancer growth and boosting the immune system. The study aims to find the safest dose and see if the combination is effective.

Who is the study for?

This trial is for young patients aged 6 months to 21 years with specific tumors lacking INI1 or SMARCA4 proteins. Eligible participants must have completed prior treatments, be in good health otherwise, and agree to contraception if applicable. Those with uncontrolled illnesses, organ transplants, pregnancy, certain infections like HIV or hepatitis B/C, autoimmune diseases requiring treatment within the past year, or a history of allergic reactions to similar compounds are excluded.

What is being tested?

The study tests a combination of three drugs: Tazemetostat (TAZVERIK), Nivolumab (OPDIVO), and Ipilimumab (YERVOY) as potential treatments for malignant rhabdoid tumor and other related conditions that lack INI1/SMARCA4 proteins. The effectiveness of this drug trio will be evaluated on different patient groups based on their disease status.

What are the potential side effects?

Potential side effects may include immune-related issues due to Nivolumab and Ipilimumab's action on the immune system; these can range from inflammation in various organs to skin reactions. Tazemetostat could cause blood disorders or fatigue. Specific side effects depend on individual responses.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am mostly able to care for myself and carry out daily activities.

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My tumor lacks INI1 or SMARCA4, confirmed by tests.

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I am between 6 months and 21 years old.

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I can understand and agree to the study's procedures and risks.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am not taking any experimental drugs or strong medications that affect liver enzymes.

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I have had or currently have lung inflammation treated with steroids.

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I have been treated with specific immune therapy drugs before.

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I have never had myeloid malignancies, MDS, LBL, or ALL.

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I have an autoimmune disease that needed treatment in the last year.

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I have a history of HIV, hepatitis B, or hepatitis C.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ treatment duration is a median of n cycles range (t1 - t2). treatment continues until disease progression or unacceptable toxicity up to 5.5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~treatment duration is a median of n cycles range (t1 - t2). treatment continues until disease progression or unacceptable toxicity up to 5.5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and treatment duration is a median of n cycles range (t1 - t2). treatment continues until disease progression or unacceptable toxicity up to 5.5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Incidence of Grade 3 or Higher Treatment-Related Toxicity

Maximal Tolerated Dose (MTD)

Secondary study objectives

Median Overall Survival (OS)

Median Progression-free survival (PFS)

Overall Response Rate (ORR)

Side effects data

From 2021 Phase 2 trial • 20 Patients • NCT03456726

53%

Dysgeusia

41%

Nasopharyngitis

29%

Upper respiratory tract infection

29%

Blood creatine phosphokinase increased

29%

Lymphopenia

29%

Constipation

29%

Stomatitis

24%

Rash

18%

Weight decreased

18%

Blood creatinine increased

18%

Thrombocytopenia

18%

Neutropenia

18%

Nausea

12%

Influenza

12%

Amylase increased

12%

Herpes simplex

12%

Malaise

12%

Pneumonia

12%

Urinary tract infection

12%

Hypertriglyceridaemia

12%

Anaemia

12%

Hypophosphataemia

12%

Alopecia

12%

Eczema

Phlebitis

Aspartate aminotransferase increased

Blood zinc decreased

Haematuria

Electrocardiogram QT prolonged

Traumatic intracranial haemorrhage

Visual field defect

Skin exfoliation

Oedema peripheral

Gastroenteritis

Impetigo

Osteonecrosis of jaw

Hypogammaglobulinaemia

Rash maculo-papular

Nail disorder

Pyrexia

Myalgia

Gamma-glutamyltransferase increased

Insomnia

Hypertonic bladder

Fatigue

Traumatic fracture

Upper respiratory tract inflammation

Blood pressure decreased

Hypoalbuminaemia

Musculoskeletal chest pain

Gastric cancer

Non-small cell lung cancer

Haematochezia

Tooth disorder

Bronchitis

Abdominal pain

Large intestine polyp

Pneumocystis jirovecii pneumonia

Alanine aminotransferase increased

Immature granulocyte count increased

Cataract

Mechanical ileus

Atypical pneumonia

Periodontitis

Pneumonia aspiration

Leukopenia

Pericardial effusion

Conjunctival haemorrhage

Visual impairment

Epigastric discomfort

Oral herpes

Paronychia

Fall

Postoperative delirium

Procedural pain

Skin laceration

Tooth fracture

Hyperglycaemia

Hyperkalaemia

Hyperuricaemia

Pain in extremity

Tendon disorder

Myelodysplastic syndrome

Muscle spasticity

Peripheral motor neuropathy

Sciatica

Syncope

Asthma

Dysphonia

Erythema multiforme

Keloid scar

100%

80%

60%

40%

20%

Study treatment Arm

Participants With Follicular Lymphoma

Participants With Diffuse Large B-cell Lymphoma

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

8Treatment groups

Experimental Treatment

Group I: Phase I b: DOSE ESCALATION (STRATUM B, NON-ATRT, NON-CNS)Experimental Treatment3 Interventions

Part 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

Group II: Phase I a: DOSE ESCALATION (STRATUM A, ATRT and primary CNS malignant tumor, INI/SMARCA4-deficient)Experimental Treatment3 Interventions

Group III: EXP B3: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA B3)Experimental Treatment3 Interventions

Once 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

Group IV: EXP B2: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA B2)Experimental Treatment3 Interventions

Group V: EXP B1: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA B1)Experimental Treatment3 Interventions

Group VI: EXP A3: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA A3)Experimental Treatment3 Interventions

Group VII: EXP A2: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA A2)Experimental Treatment3 Interventions

Group VIII: EXP A1: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA A1)Experimental Treatment3 Interventions

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Nivolumab

2015

Completed Phase 3

~4010

Ipilimumab

2015

Completed Phase 3

~3420

Tazemetostat

2016

Completed Phase 2

~1050

0 / 10Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Primary CNS Malignant Tumors include targeted therapies and immunotherapies. Tazemetostat is an EZH2 inhibitor that works by blocking the EZH2 protein, which is involved in gene expression and tumor growth. Nivolumab is a PD-1 inhibitor that prevents cancer cells from evading the immune system by blocking the PD-1 pathway, thereby enhancing the body's immune response against the tumor. Ipilimumab is a CTLA-4 inhibitor that also boosts the immune response by blocking the CTLA-4 protein, which normally downregulates immune activity. These mechanisms are significant for patients as they offer targeted approaches to disrupt tumor growth and enhance immune-mediated tumor destruction, potentially leading to better treatment outcomes.

Management of Brain Metastases in Patients With Melanoma.