PRIMARY OBJECTIVES:
I. To characterize the safety and tolerability of systemic tocilizumab, an IL-6 receptor
antagonist, in combination with Ipilimumab and nivolumab as front-line treatment for patients
with advanced cutaneous melanoma, urothelial carcinoma and in EGFR mutant non-small cell lung
cancer (NSCLC).
II. To determine the grade 3 or higher toxicity rate of Tocilizumab in combination with
Ipilimumab and nivolumab for patients with advanced cutaneous melanoma.
SECONDARY OBJECTIVES:
I. To estimate the objective response rate (ORR), defined as the proportion of patients with
complete response (CR) or partial response (PR), and durable response rate (DRR), defined as
the proportion of patients with objective responses of > 6 months duration, as determined by
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and immune related RECIST
(irRECIST).
II. To estimate progression-free survival (PFS) defined as the time from the start of
treatment to disease progression or death, whichever occurs first.
III. To estimate overall survival (OS) defined as the time from the start of treatment to
death from any cause.
EXPLORATORY OBJECTIVE:
I. To assess pre- and post-treatment blood/tumor biopsies for immunologic assessment and to
explore any potential association between biomarker measurements and antitumor activity.
OUTLINE: OUTLINE: Patients are assigned to 1 of 3 cohorts: 1=melanoma, 2=Urothelial, 3=NSCLC.
COHORT 1: Patients with melanoma will receive ipilimumab intravenously (IV) over 90 minutes
and nivolumab IV over 30 minutes on day 1. Treatment with ipilimumab and nivolumab repeats
every 3 weeks for 4 doses, then treatment with nivolumab repeats every 4 weeks for 2 years in
the absence of disease progression or unacceptable toxicity. Starting on week 1, patients
also receive tocilizumab subcutaneously (SC) every 2 weeks for up to 12 weeks (6 doses) in
the absence of disease progression or unacceptable toxicity.
COHORT 2: Patients with urothelial cancer will receive ipilimumab IV over 90 minutes and
nivolumab IV over 30 minutes on day 1. Treatment with ipilimumab and nivolumab repeats every
3 weeks for 4 doses, then treatment with nivolumab repeats every 4 weeks for 2 years in the
absence of disease progression or unacceptable toxicity. Starting on week 1, patients also
receive tocilizumab SC every 2 weeks for up to 12 weeks (6 doses) in the absence of disease
progression or unacceptable toxicity.
COHORT 3: Patients with NSCLC receive ipilimumab IV over 90 minutes every 6 weeks and
nivolumab IV over 30 minutes every 2 weeks for up to 2 years. Patients also receive
tocilizumab SC every 2 weeks for up to 12 weeks (6 doses). Treatment continues in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 2 years.
Inclusion Criteria:
- Participants must have signed and dated an Institutional Review Board
(IRB)/International Electrotechnical Commission (IEC) approved written informed
consent form in accordance with regulatory and institutional guidelines. This must be
obtained before the performance of any protocol related procedures that are not part
of normal participant care
- Participants must be willing and able to comply with scheduled visits, treatment
schedule, laboratory testing, tumor biopsies, and other requirements of the study
- All consented participants should be registered in the institutional database CORe
- COHORT 1: Histologically confirmed stage III (unresectable) or stage IV melanoma, as
per American Joint Committee on Cancer (AJCC) version 8 staging system. Patients must
consent to BRAF testing or have documented BRAF status as per regionally acceptable
V600 mutational status testing. Twenty biopsiable patients will be enrolled.
Specifically, 25 melanoma will be enrolled in expansion cohort. 20 biopsiable will
include pts in expansion cohorts
- COHORT 1: Have not received prior anti-cancer therapy for advanced or metastatic
melanoma
- COHORT 1: Treatment-naïve participants (i.e., no prior systemic anticancer therapy for
unresectable or metastatic melanoma) with the exception of prior adjuvant treatment
for melanoma with approved agents (eg, BRAF/MEK inhibitors, ipilimumab, nivolumab,
pembrolizumab or interferon). Participants who have had recurrence within the 6 months
of completing adjuvant treatment are not eligible
- COHORT 2: Histologically or cytologically documented locally advanced or transitional
cell carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, or
urethra. Patients with mixed histologies are required to have a dominant transitional
cell pattern
- COHORT 2: Enrollment of urothelial carcinoma 1st line patients who are
cisplatin-ineligible and who, after consultation with the investigator, choose to
forego front-line chemotherapy or immunotherapy
- COHORT 2: Treatment naive, cisplatin-eligible patients who refuse chemotherapy
standard of care or treatment naive, cisplatin-ineligible patients who meet at least
one of the following criteria:
- Common Terminology Criteria for Adverse Events (CTCAE) version (v)5 grade >= 2
audiometric hearing loss. CTCAE v5 grade >= 2 peripheral neuropathy.
- Cisplatin ineligibility defined as: Glomerular filtration rate (GFR) less than 60
and >= 15 mL/min or; chronic heart failure (CHF) New York Heart Association
(NYHA) class III or higher or; peripheral neuropathy grade 2 or higher or Eastern
Cooperative Oncology Group (ECOG) performance status (PS) 2 or higher or;
impaired hearing grade 2 or higher.
- GFR is either measured using a 24 hour urine, calculated using Cockcroft-Gault,
or estimated using the Modification of Diet in Renal Disease (MDRD) method from
the National Kidney Disease Education Program (NKDEP) (the method reported by MD
Anderson Cancer Center [MDACC] laboratories)
- COHORT 2: No prior chemotherapy for inoperable locally advanced or metastatic
urothelial carcinoma
- COHORT 2: Prior local intravesical chemotherapy is allowed if completed at least 4
weeks prior to the initiation of study treatment
- COHORT 2: For patients who received prior adjuvant/neoadjuvant chemotherapy or
chemo-radiation for urothelial carcinoma, a treatment-free interval of more than 12
months between the last treatment administration and the date of recurrence is
required to be considered treatment naive in the metastatic setting. Patients must not
have received neoadjuvant or adjuvant therapy with any immuno-oncology regimens.
Please note that this small population of patients will be excluded
- COHORT 3: Subjects diagnosed with histologically or cytologically confirmed locally
advanced/metastatic NSCLC with EGFR mutation known to be associated with EGFR tyrosine
kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
- Subjects must have received one prior line of therapy with an EGFR TKI in the
locally advanced/metastatic setting
- COHORT 3: Subjects need to meet either A or B. A) Must have received and progressed on
an approved first or second generation EGFR TKI (eg, erlotinib or gefitinib [first
generation] or afatinib [second generation]) and must be T790M negative by an approved
testing assay on tumor biopsy at the time of progression. B) Patient must have
received third generation TKI Osimertinib and progressed on this therapy for study
entry. C) TKI needs to be the last therapy. D) Prior chemotherapy received in the
neoadjuvant or adjuvant settings will not be considered a line of therapy
- Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status
of =< 1 (adults 18 years or older)
- Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per
RECIST 1.1 criteria
- Participants with stable brain metastases =< 3 cm, with no clinical requirement for
local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic
therapy are allowed to enroll. Subjects must be free of neurologic signs and symptoms
related to metastatic intracranial lesions and must not have required or received
systemic corticosteroid therapy within 10 days prior to first treatment
- All participants must have tissue submitted during screening. Either a formalin-fixed,
paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, obtained
within 3 months prior to enrollment. Biopsy should be excisional, incisional, punch
biopsy, core needle or surgical specimen. Fine needle aspiration is unacceptable for
submission. Biopsies of bone lesions that do not have a soft tissue component are also
unacceptable for submission
- Prior palliative radiotherapy must be completed at least 2 weeks prior to day 1 of
study treatment. Participants must have recovered from all radiation-related
toxicities. Note: radiated lesions cannot be used as measurable lesions unless there
is clear evidence of progression
- Participants must be able and willing to comply with the study visit schedule and
study procedures
- A documented left ventricular ejection fraction (LVEF) > 45% using standard
echocardiogram or multigated acquisition (MUGA) scan test within 60 days prior to
study treatment initiation
- Males and females, ages 18 years or older
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours prior to the start of study treatment
- Women must not be breastfeeding
- Women of childbearing potential (WOCBP) must agree to follow instructions for
method(s) of contraception for the duration of treatment with study treatment and for
5 months post- treatment completion. Women should use an adequate method(s) of
contraception
- Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with study treatment(s) and 7
months post-treatment completion. In addition, male participants must be willing to
refrain from sperm donation during this time. Men who are sexually active with WOCBP
must agree to follow instructions for method(s) of contraception
- Azoospermic males are exempt from contraceptive requirements. WOCBP who are
continuously not heterosexually active are also exempt from contraceptive
requirements, and still must undergo pregnancy testing as described in this section
Exclusion Criteria:
- Active brain metastases or leptomeningeal metastases. Participants with brain
metastases are eligible if these have been treated and there is no MRI evidence of
progression for at least 4 weeks after treatment is complete and within 28 days prior
to first dose of study treatment administration. There must also be no requirement for
immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone
equivalents) for at least 2 weeks prior to study treatment administration. Stable dose
of anticonvulsants is allowed. Treatment for central nervous system (CNS) metastases
may include stereotactic radiosurgery (e.g. GammaKnife, CyberKnife, or equivalent) or
neurosurgical resection. Patient who received whole brain radiation therapy are not
eligible
- Subjects with interstitial lung disease that is symptomatic or may interfere with the
detection or management of suspected drug-related pulmonary toxicity
- Uveal and mucosal melanoma are excluded
- Any condition including medical, emotional, psychiatric, or logistical that, in the
opinion of the Investigator, would preclude the patient from adhering to the protocol
or would increase the risk associated with study participation or study drug
administration or interfere with the interpretation of safety results (eg, a condition
associated with diarrhea or acute diverticulitis)
- Prior malignancy active within the previous 3 years except for locally curable cancers
that have been apparently cured, such as basal or squamous cell skin cancer,
superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
- Participants with an active, known or suspected autoimmune disease. Participants with
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment,
or conditions not expected to recur in the absence of an external trigger are
permitted to enroll
- Participants with a condition requiring systemic treatment with either corticosteroids
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of start of week 1 day 1. Inhaled or topical steroids, and adrenal replacement
steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of
active autoimmune disease
- History of organ transplant or tissue that requires systemic use of immune suppressive
agents
- Active infection requiring systemic therapy within 14 days prior to week 1 day 1
- Known cardiac history including:
- History of unstable or deteriorating cardiac disease within the previous 12
months prior to screening including but not limited to the following:
- Unstable angina or myocardial infarction
- Transient ischemic attack (TIA)/cerebrovascular accident (CVA)
- Congestive heart failure (New York Heart Association [NYHA] class III or IV)
- Uncontrolled clinically significant arrhythmias
- Known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at
sites where mandated locally
- Use of an investigational agent or an investigational device within 28 days before
administration of first dose of study drug
- Participants who have received a live / attenuated vaccine within 30 days before first
treatment
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
pathways with the exception of treatment with adjuvant intent
- Participants with history of life-threatening toxicity related to prior immune therapy
(eg. anti- CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug
specifically targeting T- cell co-stimulation or immune checkpoint pathways) except
those that are unlikely to re-occur with standard countermeasures (e.g.. hormone
replacement after adrenal crisis)
- Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese
medicines) intended for general health support or to treat the disease under study
within 2 weeks prior to study treatment initiation
- Whole blood cell (WBC) < 2000/uL (may not transfuse within 14 days of study treatment
initiation)
- Neutrophils < 1500/uL (may not transfuse within 14 days of study treatment initiation)
- Platelets < 100,000/uL (may not transfuse within 14 days of study treatment
initiation)
- Hemoglobin < 9.0 g/dL (may not transfuse within 14 days of study treatment initiation)
- Serum creatinine > 1.5 x upper limit of normal (ULN), unless creatinine clearance >=
40 mL/min (measured or calculated using the Cockcroft-Gault formula)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): > 3.0 x ULN
- Total bilirubin > 1.5 x ULN (except participants with Gilbert syndrome who must have a
total bilirubin level of < 3.0 x ULN)
- Any positive test result for hepatitis B virus or hepatitis C virus indicating
presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen)
positive, or hepatitis C antibody (anti-hepatitis C virus [HCV]) positive (except if
HCV-ribonucleic acid [RNA] negative)
- History of allergy or hypersensitivity to study drug components
- History of severe hypersensitivity reaction to any monoclonal antibody
- Known hypersensitivity to tocilizumab, ipilimumab, or nivolumab
- Prisoners or participants who are involuntarily incarcerated. (Note: under certain
specific circumstances a person who has been imprisoned may be included or permitted
to continue as a participant
- Participants who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness
