- Written informed consent and HIPAA authorization for release of personal health
information prior to registration. NOTE: HIPAA authorization may be included in the
informed consent or obtained separately.
- Age ≥ 18 years at the time of consent.
- Histologically or cytologically confirmed non-squamous, non-small cell lung cancer
- Locally advanced or metastatic disease, not amenable to curative surgery or
- Patients must have one of the following:
- NSCLC which harbors Epidermal Growth Factor Receptor (EGFR) Exon 19 deletion.
- NSCLC which harbors EGFR L858R mutation. EGFR deletion/mutation must be
documented by a Clinical Laboratory Improvement Amendments (CLIA) certified test
(either from tissue or ctDNA from blood is allowed). If EGFR deletion/mutation
testing has not been done, it should be ordered per standard of care.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix A)
- Measurable disease per RECIST 1.1
- Patients with brain metastases are eligible if they are asymptomatic, are treated, or
are neurologically stable for at least two weeks without the use of steroids or on
stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent). These criteria
must be met on day of consent.
- Ability to take pills by mouth
- Previous treatment with cytotoxic chemotherapy or immunotherapy is allowed
- Patients must have adequate hematologic, coagulation, hepatic, and renal function. All
laboratory tests must be obtained less than 4 weeks from study entry. This includes:
- Absolute Neutrophil Count (ANC) >/= 1,500/mm3
- platelet count >/=100,000/mm3
- Hemoglobin (HgB) ≥ 9 g/dL (may be with transfusion)
- Creatinine ≤ 1.5x ULN or creatinine clearance (measured via 24-hour urine
collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times the ULN, a
24-hour urine collection to calculate creatinine clearance must be performed).
- The patient's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA); if
urine dipstick or routine analysis is ≥ 2+, a 24-hour urine collection for
protein must demonstrate < 1000 mg of protein in 24 hours to allow participation
in this protocol).
- International Normalized Ratio (INR) ≤ 1.5 and a partial thromboplastin time
(PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy).
Patients receiving warfarin must be switched to low molecular weight heparin and
have achieved stable coagulation profile prior to first dose of protocol therapy.
- Total Serum Bilirubin ≤ 1.5 x ULN (Patients with known Gilbert Syndrome, a total
bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
- Serum Glutamic Oxaloacetic Transaminase (SGOT), Serum Glutamic-Pyruvic
Transaminase (SGPT) ≤ 3 X ULN if no liver metastasis present
- SGOT, SGPT ≤ 5 X ULN if liver metastasis present
- Females of childbearing potential must not be breast feeding and must have a negative
serum pregnancy test within 7 days of starting of treatment. The patient must agree to
use adequate contraception for a minimum of two weeks prior to receiving study
medication until 3 months after discontinuation of the study medication. Acceptable
methods of contraception are listed in Section 5.5. NOTE: Women will be considered
post-menopausal if they have been amenorrheic for the past 12 months without an
alternative medical cause. The following age-specific requirements must also apply:
Women < 50 years old: they would be considered post-menopausal if they have been
amenorrheic for the past 12 months or more following cessation of exogenous hormonal
treatments. The levels of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone
(FSH) must also be in the post-menopausal range (as per the institution). Women ≥ 50
years old: they would be considered post-menopausal if they have been amenorrheic for
the past 12 months or more following cessation of all exogenous hormonal treatments,
or have had radiation-induced oophorectomy with the last menses > 1 year ago, or have
had chemotherapy-induced menopause with >1 year interval since last menses, or have
had surgical sterilization by either bilateral oophorectomy or hysterectomy.
- Non-sterilized males who are sexually active with a female partner of childbearing
potential must use adequate contraception for the duration of the study and 4 months
after the last dose of study medication. If male patients wish to father children they
should be advised to arrange for freezing of sperm samples prior to the start of the
- Previous treatment with any EGFR TKIs, including erlotinib, gefitinib, afatinib,
avitinib, dacomitinib, rociletinib, or osimertinib.
- Previous treatment with any anti-Vascular Endothelial Growth Factor (VEGF)
medications, including vandetinib, nintedanib, bevacizumab, or ramucirumab.
- Patients currently receiving (or unable to stop use prior to receiving the first dose
of study treatment) medications or herbal supplements known to be potent inducers of
CYP3A4 (at least 3 weeks prior). All patients must try to avoid concomitant use of any
medications, herbal supplements and/or ingestion of foods with known inducer effects
- Spinal cord compression unless asymptomatic or stable for at least 2 weeks prior to
start of study treatment.
- Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the
exception of alopecia grade 2) at the time of starting study treatment.
- Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses, which in the investigator's opinion makes
it undesirable for the subject to participate in the trial or which would jeopardize
compliance with the protocol, or active infection including hepatitis B, hepatitis C
and human immunodeficiency virus (HIV). Screening for chronic conditions is not
- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of osimertinib.
- Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active
interstitial lung disease.
- Patients with uncharacterized eye disorders.
- Males and females of reproductive potential who are not using and effective method of
birth control and females who are pregnant or breastfeeding or have a positive (urine
or serum) pregnancy test prior to study entry.
- History of hypersensitivity of osimertinib or ramucirumab (or active or inactive
excipients of osimertinib or ramucirumab)
- Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and requirement.
- Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc using Fridericia's formula) > 470 msec
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG e.g., complete left bundle branch block, third degree heart block,
second degree heart block, PR interval >250msec
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age in
first degree relatives or any concomitant medication known to prolong the QT
- The patient has experienced any arterial thromboembolic events, including but not
limited to myocardial infarction, transient ischemic attack, cerebrovascular
accident, or unstable angina, within 6 months prior to first dose of protocol
- The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg
systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical
- The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first
dose of protocol therapy.
- The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or
any other significant thromboembolism (venous port or catheter thrombosis or
superficial venous thrombosis are not considered "significant") during the 3 months
prior to first dose of protocol therapy.
- The patient has cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any
degree) and a history of hepatic encephalopathy or clinically meaningful ascites
resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from
cirrhosis requiring diuretics or paracentesis.
- Any hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior
to first dose of protocol therapy or with radiographic evidence of intratumor
cavitation or has radiologically documented evidence of major blood vessel invasion or
encasement by cancer.
- The patient has a prior history of GI perforation/fistula (within 6 months of first
dose of protocol therapy) or risk factors for perforation.
- The patient has a serious or nonhealing wound, ulcer, or bone fracture within 28 days
prior to first dose of protocol therapy.
- The patient has undergone major surgery within 28 days prior to first dose of protocol
therapy, or minor surgery/subcutaneous venous access device placement within 7 days
prior to the first dose of protocol therapy. The patient has elective or planned major
surgery to be performed during the course of the clinical trial.
- The patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal
anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others),
dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose
325 mg/day) is permitted.