This is a prospective, open label, interventional trial beginning with a phase 1b safety
run-in followed by an expansion cohort.
Inclusion Criteria:
- Male or female subject aged ≥ 18 years.
- Histologically or cytologically confirmed metastatic, non-small cell lung cancer
(NSCLC).
- The presence of any sensitizing epidermal growth factor receptor (EGFR) tumor
mutation.
- Currently on a stable dose of osimertinib (40 mg or 80 mg daily) ≥ 28 days without
clinical disease progression.
- ECOG Performance Status ≤ 2.
- Adequate organ function as defined as:
- Hematologic:
- White blood cell count > 2.0 k/uL
- Platelet count > 100,000/mm3
- Hemoglobin ≥ 9 g/dL
- Absolute neutrophil count (ANC) ≥ 1,000/mm3
- Hepatic:
- Total Bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
- Except for patient with Gilbert's syndrome.
- AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN
- Renal:
- eGFR ≥ 30 mL/min/1.73m2 or creatinine clearance ≥ 30 mL/min by
Cockcroft-Gault:
- Males: ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72)
- Females: (((140-age)×weight[kg])/(serum creatinine [mg/dL]×72))×0.85
- Concurrent enrollment in the study, "Rethinking Measurement of Performance Status in
Cancer Patients," IRB 112529.
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).
- Highly effective contraception for both male and female subjects throughout the study
and for at least 5 months after the last dose of study therapy for females and 7
months after the last dose for males if the risk of conception exists.
- Recovery to baseline or ≤ Grade 1 CTCAE v.5 from toxicities related to any prior
treatments, unless AE(s) are clinically non-significant and/or stable on supportive
therapy.
- Able to provide informed consent and willing to sign an approved consent form that
conforms to federal and institutional guidelines.
Exclusion Criteria:
- Prior EGFR targeted therapy.
- Prior radiation therapy within 2 weeks prior to cycle one day one.
- Active or prior autoimmune disease that might deteriorate when receiving an
immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or
hypo-or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
- Known history of:
- Immune-mediated colitis, inflammatory bowel disease, or interstitial lung
disease/pneumonitis.
- Intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are
known risk factors for bowel perforation.
- Current use of immunosuppressive medication at the time of study enrollment, EXCEPT
for the following permitted steroids:
- Intranasal, inhaled, topical steroids, eye drops or local steroid injection
(eg,intra-articular injection);
- Systemic corticosteroids at physiologic doses ≤ 10mg/day of prednisone or
equivalent;
- Steroids as premedication for hypersensitivity reactions (e.g., computed
tomography (CT) scan premedication).
- Diagnosis of any other malignancy within 2 years prior to study enrollment, except for
adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the
breast, bladder or of the cervix, and low-grade (Gleason 6 or below) prostate cancer
on surveillance with no plans for treatment intervention (e.g., surgery, radiation, or
castration) or prostate cancer that has been adequately treated with prostatectomy or
radiotherapy and currently with no evidence of disease or symptoms is allowed.
- Uncontrolled CNS metastases are not allowed; subjects with previously treated brain
metastases will be allowed if the brain metastases have been treated, toxicities have
resolved to grade 1 or baseline and steroids are no longer required. Leptomeningeal
metastases are not allowed.
- Patients with asymptomatic brain metastasis are allowed if previous steroid
treatment was discontinued ≥ 6 weeks.
- Patients with stable brain metastases on osimertinib therapy are eligible.
- Palliative radiation therapy is allowed while on study therapy (see Section 6.4).
- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of
cardiac function using the New York Heart Association Functional Classification.
To be eligible for this trial, patients should be class 2B or better.
- Myocardial infarction, severe angina, or unstable angina within 6 months prior to
administration of first dose of study drug.
- Uncontrolled symptomatic hypertension that cannot be controlled with
anti-hypertensive agents.
- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation).
- Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial
fibrillation that is well controlled with anti-arrhythmic medication).
- Coronary or peripheral artery bypass graft within 6 months of screening.
- QTc prolongation > 500 msec.
- Active, clinically symptomatic left ventricular failure (left ventricle ejection
fraction (LVEF) < 50%).
- Other clinically significant disorders that would preclude safe study
participation.
- Known HIV infection with a detectable viral load within 6 months of the anticipated
start of treatment.
-Note: Patients on effective anti-retroviral therapy with an undetectable viral load
within 6 months of the anticipated start of treatment are eligible for this trial.
- Known chronic hepatitis B virus (HBV) or hepatitis C virus infection with a detectable
viral load.
-Note: Patients with an undetectable HBV viral load on appropriate suppressive therapy
are eligible. Patients with an undetectable HCV viral load on appropriate treatment
are eligible.
- Vaccination with a live attenuated vaccine within 4 weeks of cycle one day one and
while on trials is prohibited except for administration of inactivated vaccines.
- Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v5.0 Grade ≥ 3).
- Subjects taking prohibited medications as described in Section 6.4.2. A washout period
of prohibited medications for a period of at least 5 half-lives or as clinically
indicated should occur prior to the start of treatment.
- Subject is a prisoner or involuntarily incarcerated or is compulsorily detained for
treatment of either a psychiatric or physical illness (e.g. infectious disease).
