Immunotherapy (Nivolumab and Ipilimumab) for the Treatment of Aggressive Pituitary Tumors
This phase II trial studies how well nivolumab and ipilimumab work in treating pituitary tumors that form, grow, or spread quickly (aggressive). Nivolumab blocks the protein PD-1, which can act as a brake on the immune system. Blocking PD-1 releases the brakes, so the immune system can recognize tumor cells and kill them. Ipilimumab acts against a protein called CTLA-4, which can slow down or turn off the immune system. Blocking CTLA-4 allows the body to have an immune reaction that helps destroy tumor cells. The purpose of this study is to find out whether the study drugs, nivolumab and ipilimumab, are an effective treatment for people with pituitary tumors.
Inclusion Criteria
- A pituitary adenoma/carcinoma of any histology * Patients with unresectable tumors that are radiographically (and/or biochemically) consistent with a pituitary adenoma may be considered for enrollment without pathologic confirmation with approval from the principal investigator
- Progression on imaging following radiotherapy * Patients with pituitary carcinomas in whom there is not felt to be a palliative benefit to treatment with radiotherapy are eligible for enrollment without prior radiotherapy
- Measurable disease by RANO criteria
- At least 4 weeks have elapsed since the patient last received temozolomide and the patient must have recovered hematologically from other chemotherapeutics
- Karnofsky performance status (KPS) greater than or equal to 70, or Eastern Cooperative Oncology Group (ECOG) 0 or 1
- White blood cells (WBC) >= 2000/uL
- Neutrophils >= 1500/uL
- Platelets >= 100 x 10^3/uL
- Hemoglobin > 9.0 g/dL
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
- Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
- Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min using the Cockcroft-Gault formula
- Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug * WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. Women who are not of childbearing potential are not required to use contraception * Women of childbearing potential must have a negative serum or urine pregnancy test upon study entry
- Men who are sexually active with women of childbearing potential must use adequate contraception upon study entry until 31 weeks after the last dose of study treatment. Men who are surgically sterile or azoospermic do not require contraception
Exclusion Criteria
- A corticosteroid requirement of greater than 4 mg per day of dexamethasone (or an equivalent dose) * NOTE: Patients requiring a physiologic replacement dose of corticosteroids, who may require stress dose corticosteroids, due to adrenal insufficiency are permitted onto this trial
- Active, known, or suspected autoimmune disease within the past 2 years * NOTE: Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
- Patients should be excluded if they have had prior systemic treatment with a CTLA-4 antibody. Prior treatment with PD1 or PD-L1 antibodies are permitted as long as the patient did not experience serious toxicities requiring treatment discontinuation related to prior PD-1 or PD-L1 therapy
- Patients should be excluded if they have a known history of testing positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus antibody (HCV antibody) indicating acute or chronic infection
- Patients should be excluded if they have a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- History of allergy to study drug components
- History of severe hypersensitivity reaction to any monoclonal antibody
- Women who are pregnant or breast-feeding
- Inability to undergo radiographic surveillance
Additional locations may be listed on ClinicalTrials.gov for NCT04042753.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To assess the radiographic response rate by Response Assessment in Neuro-Oncology Criteria (RANO)/immunotherapy (i)RANO during the first 36 weeks on treatment with combination ipilimumab (3 mg/kg every [q]3 weeks) and nivolumab (1 mg/kg q3 weeks) for 4 cycles, followed by nivolumab (480 mg q4 weeks) for 6 cycles with the option of continuing until progression of disease or until the study closes, whichever occurs first, in patients with treatment-refractory, recurrent pituitary tumors.
SECONDARY OBJECTIVES:
I. To assess the radiographic response at each imaging time point by a volumetric criteria.
II. To assess safety and tolerability as assessed by Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 of ipilimumab and nivolumab in the treatment of aggressive pituitary tumors.
III. To assess the biochemical response (> 50% decrease in hormonal secretion) of functional pituitary tumors to treatment with ipilimumab and nivolumab.
IV. To determine progression free and overall survival.
EXPLORATORY OBJECTIVES:
I. Correlate PD-L1/CTLA4 expression and mutational burden/microsatellite instability as assessed by IMPACT with treatment response.
II. Correlate the activation and exhaustion status of different T cell populations within peripheral blood mononuclear cells and the mutational burden/microsatellite instability of the tumor with clinical response in patients accrued at Memorial Sloan Kettering Cancer Center (MSK).
III. Quantify the effect of aggressive pituitary tumors on quality of life and the effect of the treatment on quality of life.
OUTLINE:
Patients receive nivolumab intravenously (IV) over 1 hour and ipilimumab IV over 1.5 hours on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, patients receive nivolumab IV over 1 hour on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may then continue to receive treatment at the discretion of the principal investigator.
After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorAndrew Lee Lin
- Primary ID19-216
- Secondary IDsNCI-2019-05418
- ClinicalTrials.gov IDNCT04042753