| Eligibility |
Inclusion Criteria
1) Signed Written Informed Consent
1. Participants must have signed and dated an IRB/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.
2. Participants must be willing and able to comply with scheduled visits, treatment
schedule, laboratory testing, tumor biopsies, and other requirements of the study.
3. All consented participants should be registered in the institutional database CORe 2)
Type of Participant and Target Disease Characteristics
Cohort 1:
Melanoma (n=35 patients)
1. Histologically confirmed stage III (unresectable) or stage IV melanoma, as per
American Joint Committee on Cancer (AJCC) Version 8 staging system (Appendix A).
Patients must consent to BRAF testing or have documented BRAF status as per
regionally acceptable V600 mutational status testing. Specifically, 10 melanoma
patients will be initially enrolled, and an additional 25 melanoma patients will
be enrolled in expansion cohort. Patients with biopsiable disease will have
tissue collected including patients in the expansion cohorts. Archival tumor
tissue samples may be collected in place of the biopsy after PI consultation. If
biopsy is not feasible, or the patient declines to participate due to the biopsy,
the patient may still enroll with PI approval.
2. Treatment-naïve participants (ie, 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:
Urothelial Carcinoma (n=10 patients) 1. 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.
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.
3. Treatment naïve, 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) v5 Grade = 2 audiometric
hearing loss. CTCAE v5 Grade = 2 peripheral neuropathy.
- Cisplatin ineligibility defined as: GFR less than 60 and = 15 mL/min or; CHF NYHA
class III or higher or; peripheral neuropathy grade 2 or higher or ECOG PS 2 or
higher or; impaired hearing grade 2 or higher.
- GFR is either measured using a 24 hour urine, calculated using Cockroft-Gault, or
estimated using the MDRD method from the National Kidney Disease Education
Program (NKDEP) (the method reported by MDACC laboratories).
a. Cockroft-Gault formula: CLcr = [(140-age) • wt(kg)]/[72 •Creat (mg/dL)]
(Multiply by 0.85 for females).
4. No prior chemotherapy for inoperable locally advanced or metastatic urothelial
carcinoma.
5. Prior local intravesical chemotherapy is allowed if completed at least 4 weeks
prior to the initiation of study treatment.
6. 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: (n=10 patients)
1. Subjects diagnosed with histologically or cytologically confirmed locally
advanced/metastatic NSCLC with EGFR mutation known to be associated with EGFR TKI
sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
2. Subjects must have received one prior line of therapy with an EGFR TKI in the
locally advanced/metastatic setting.
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.
Common Inclusion Criteria for all three Cohorts
1. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance
status less than or equal to 1 (adults 18 years or older).
2. Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI)
per RECIST 1.1 criteria.
3. Participants with stable brain metastases <=3cm, 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.
4. 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. If the patient refuses the biopsy, the
patient may still enroll with PI approval.
5. Prior palliative radiotherapy is allowed. Radiation-related toxicities should have
resolved to grade 1 or less prior to study entry. Please note that radiated lesions
cannot be used as measurable lesions unless there is clear evidence of progression 6.
Participants must be able and willing to comply with the study visit schedule and
study procedures.
3) Age and Reproductive Status
1. Males and females, ages 18 years or older
2. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
the start of study treatment.
3. Women must not be breastfeeding
4. 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.
5. 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.
6. 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.
Investigators shall counsel WOCBP, and male participants who are sexually active with
WOCBP, on the importance of pregnancy prevention and the implications of an unexpected
pregnancy. Investigators shall advise on the use of highly effective methods of
contraception, which have a failure rate of < 1% when used consistently and correctly.
Exclusion Criteria
1) Medical Conditions
a) Subjects with interstitial lung disease that is symptomatic or may interfere with the
detection or management of suspected drug-related pulmonary toxicity.
b) Uveal melanoma is excluded. c) 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).
d) 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.
e) 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.
f) 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 0 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. Please see Section 4.3for permitted therapies.
g) History of organ transplant or tissue that requires systemic use of immune suppressive
agents h) Active infection requiring systemic therapy within 14 days prior to week 0 day 1.
i) Known cardiac history including: i) History of unstable or deteriorating cardiac disease
within the previous 12 months prior to screening including but not limited to the
following:
(1) Unstable angina or myocardial infarction (2) Transient ischemic attack
(TIA)/Cerebrovascular accident (CVA) (3) Congestive heart failure (New York Heart
Association [NYHA] Class III or IV) (4) Uncontrolled clinically significant arrhythmias j)
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.
2) Prior/Concomitant Therapy
a) Use of an investigational agent or an investigational device within 28 days before
administration of first dose of study drug b) Participants who have received a live /
attenuated vaccine within 30 days before first treatment c) 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 as described in inclusion 2a.
d) Participants with history of life-threatening toxicity related to prior immune therapy
(e.g. 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) e) Treatment with botanical preparations (eg, 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.
3) Physical and Laboratory Test Findings
1. WBC < 2000/µL
2. Neutrophils < 1500/µL
3. Platelets < 100,000/µL
4. Hemoglobin < 9.0 g/dL NOTE: May not transfuse within 14 days of study treatment
initiation to meet eligibility criteria 3a through 3d.
5. Serum creatinine > 1.5 x ULN, unless creatinine clearance = 40 mL/min (measured or
calculated using the Cockroft-Gault formula) Female CLcr = (140- age in years) x
weight in kg x 0.85 72 x serum creatinine in mg/ dL Male CLcr = (140- age in years) x
weight in kg x 1.00 72 x serum creatinine in mg/ dL
6. AST/ALT: > 3.0 x ULN
7. Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a
total bilirubin level of < 3.0x ULN)
8. Any positive test result for hepatitis B virus or hepatitis C virus indicating
presence of virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen)
positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative).
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components b) History of severe
hypersensitivity reaction to any monoclonal antibody c) Known hypersensitivity to
Tocilizumab, Ipilimumab, or Nivolumab.
5) Other Exclusion Criteria
1. 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.
2. Participants who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of
the study participants and that the results of the study can be used. It is imperative that
participants fully meet all eligibility criteria.
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