Immunotherapy (Nivolumab and Ipilimumab) for the Treatment of Relapsed or Refractory INI-1 Negative Cancer
Brain & Spinal Cord Tumor
6 Months - 40 Years, Male and Female
This phase II trial investigates how well nivolumab and ipilimumab work in treating patients with INI-1 negative cancer that has come back (relapsed) or has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
I. To estimate the objective response rate (ORR) of nivolumab in combination with ipilimumab separately in each of the two strata of children and young adults with INI1-negative cancers, as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for Stratum 1 and Response Assessment in Neuro-Oncology Criteria (RANO) for Stratum 2 per local assessment.
I. To estimate the progression-free survival (PFS) and overall survival (OS) rates of patients with INI1-negative cancers treated with nivolumab and ipilimumab in each stratum and across both strata.
II. To estimate the disease control rate at 12 months in patients with INI1-negative cancers treated with nivolumab and ipilimumab in each stratum and across both strata.
III. To describe the toxicities of nivolumab given in combination with ipilimumab in children and young adults with INI1-negative cancers.
I. To describe biologic activity of study treatment as measured by correlative immunologic studies and to evaluate biomarkers of treatment response.
Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, patients receive nivolumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 14 cycles (12 months) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 2 years.
- All participants must have one of the following histologically confirmed tumors at original diagnosis or relapse:
* Stratum 1
** Malignant rhabdoid tumor (MRT)
** Rhabdoid tumor of the kidney (RTK)
** Epithelioid sarcoma
** Chordoma (poorly differentiated or de-differentiated)
** Other INI1-negative or SMARCA4-deficient malignant tumors (with principal investigator [PI] approval)
* Stratum 2
** Atypical teratoid rhabdoid tumor (ATRT)
** Other INI1-negative or SMARCA4-deficient primary central nervous system (CNS) malignant tumors (with PI approval)
- All participants must have tumor assessment at original diagnosis or relapse showing 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 bi-allelic SMARCA4 loss or mutation when SMARCA4 is equivocal or unavailable
- Age >= 6 months and =< 40 years
- Relapsed or refractory disease and no standard treatment options as determined by locally or regionally available standards of care and treating physician’s discretion
- Measurable disease as defined by
* RECIST version (v)1.1 for Stratum 1 OR
* RANO for Stratum 2
- Karnofsky performance status >= 50% for participants >= 16 years of age and Lansky performance status >= 50% for participants < 16 years of age
- Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy. Participants must meet the following minimum washout periods prior to first day of study treatment:
* Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive chemotherapy
** At least 14 days after local palliative radiation therapy (XRT) (small port)
** At least 90 days must have elapsed after prior total body irradiation (TBI), craniospinal XRT or if > 50% radiation of pelvis
** At least 42 days must have elapsed if other substantial BM radiation
** At least 42 days must have passed since last radionuclide therapy (e.g. samarium or radium)
* Small molecule biologic therapy: At least 7 days following the last dose of a nonmonoclonal biologic agent
* Monoclonal antibody: At least 21 days after the last dose
* Myeloid growth factors: At least 14 days following the last dose of long-acting growth factor (e.g. Neulasta) or 7 days following short-acting growth factor
* Stem cell or autologous T cell infusion: At least 42 days must have elapsed after stem cell or autologous T cell infusion
- Absolute neutrophil count >= 500/uL
- Platelets >= 50,000/uL and transfusion independent, defined as not receiving a platelet transfusion for at least 7 days prior to CBC documenting eligibility
- Total bilirubin =< 1.5 x upper limit of normal for age
- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x upper limit of normal (for the purpose of this study, the upper limit of normal [ULN] for ALT is 45 U/L)
- A serum creatinine based on age/gender as follows OR creatinine clearance >= 70 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
* Age: Maximum Serum Creatinine (mg/dL)
* 6 months to 1 year: 0.5 (male and female)
* 1 to < 2 years: 0.6 (male and female)
* 2 to < 6 years: 0.8 (male and female)
* 6 to < 10 years: 1 (male and female)
* 10 to < 13 years: 1.2 (male and female)
* 13 to < 16 years: 1.5 (male), 1.4 (female)
* >= 16 years: 1.7 (male), 1.4 (female)
- No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficient and a pulse oximetry > 92% while breathing room air
- Serum lipase =< ULN at baseline
- Negative beta-human chorionic gonadotropin (B-HCG) pregnancy test (urine or serum) in females of childbearing potential. Must be drawn or repeated within 24 hours prior to initial administration of nivolumab
- Women of childbearing potential (WOCBP) receiving nivolumab agree to adhere to contraception for a period of 5 months after the last dose of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will agree to adhere to contraception for a period of 7 months after the last dose of nivolumab
- Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, documented using an institutionally approved informed consent procedure
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