Cohort A in this study will enroll Immuno-oncology (IO) naïve patients who have progressed on
previous chemotherapy or targeted therapies. The subjects will be randomized 2:1(combination:
nivolumab monotherapy), with primary endpoint of 6-months PFS.
Cohort B will enroll patients with prior IO therapy (alone or in combination with
chemotherapy or in combination with other IO agents), into a non-randomized combination
trial, with primary endpoint of disease control rate.
1. Patients must have histologically or cytologically confirmed, refractory or recurrent,
advanced non-small cell lung carcinoma regardless of histology.
2. Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension in accordance with RECIST criteria v.
1.1 as described in detail in section 11.0
3. Patients must have completed one line of prior therapy in both cohorts. For
participation in the Cohort A, they must have completed at least 4 cycles of platinum
doublet therapy. For participation in Cohort B, they must have received PD-1, PD-L1
and/or CTLA-4 immunotherapy, alone or in combination with chemotherapy or in
combination with other IO agents. Treatment on this protocol may begin as long as the
patient has recovered from toxicities of prior therapy at the discretion of the
treating physician. A washout period of at least 2 weeks is required prior to starting
on this trial.
4. Patients with molecular targets (EGFR, ALK, ROS1) who have progressed on targeted
agents and are not eligible for other treatments or trials specific for this
population are allowed.
5. Age > 18 years.
6. ECOG performance status 0 or 1
7. Patients must have normal organ and marrow function as defined below. Patients should
be able to maintain ANC levels without the need for G-CSF transfusion. If blood
transfusion is performed for achieving hemoglobin levels, the levels should stay at ≥
9.0 mg/ml for at least a week after transfusion.
Absolute neutrophil count > 1,500/mcL Hemoglobin ≥ 9.0 mg/ml Platelets > 100,000/mcL
Total bilirubin ≤1.5 X institutional upper limit of normal (ULN) AST/ALT (SGOT/SGPT) <
3 times institutional normal limits, or up to 5 times institutional normal limits if
the patient has liver metastases Creatinine OR Creatinine clearance ≤1.5 X ULN, OR >
40 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal as
per Cockcroft-Gault formula International Normalized Ratio (INR) or Prothrombin Time
(PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT
is within therapeutic range of intended use of anticoagulants Activated Partial
Thromboplastin Time (aPTT) <1.5 X ULN unless subject is receiving anticoagulant
therapy as long as PT or PTT is within therapeutic range of intended use of
8. Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14
days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving
warfarin, the patient must have an INR ≤3.0. For heparin and LMWH there should be no
active bleeding (that is, no bleeding within 14 days prior to first dose of protocol
therapy) or pathological condition present that carries a high risk of bleeding (for
example, tumor involving major vessels or known varices).
9. Ability to understand and willingness to sign a written informed consent and HIPAA
10. A core tumor biopsy obtained after progression on the last treatment must be available
at study entry for the study. The biopsy sample must not be more than 90 days old at
the time of registration and the sample must be adequate for analyses. If the sample
is not adequate patient must agree to provide a fresh biopsy specimen before the start
of treatment. Any available archival tissue will also be collected.
11. The patient's urinary protein must be ≤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).
12. Female subject of childbearing potential should have a negative serum pregnancy within
72 hours prior to receiving the first dose of study medication.
13. Female subjects of childbearing potential and male subjects must be willing to use an
effective method of contraception - Contraception, for the course of the study through
150 days after the last dose of study medication.
14. Male patients who have women of child bearing potential (WOCBP) partners must agree to
use effective method of contraception - Contraception, for the course of the study
through 210 days after the last dose of study medication.
15. Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
1. Patients who have not recovered from their most recent chemotherapy or radiotherapy
prior to entering the study at the discretion of investigators. Patients may not be
currently receiving any other investigational agents or immunomodulatory agents (e.g.
ipilimumab). Patients treated with prior PD-1 or PD-L1 directed therapies are
ineligible Cohort A.
2. Prior ramucirumab treatment
3. The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first
dose of protocol therapy.
4. 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.
5. 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.
6. 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 therapy.
7. The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or
> 100 mmHg diastolic for >4 weeks) despite standard medical management.
8. The patient with history of 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 intra-tumor cavitation or has radiologically documented evidence of major blood
vessel invasion or encasement by cancer.
9. The patient has a serious or non-healing wound, ulcer, or bone fracture (as per
physician's discretion) within 28 days prior to first dose of protocol therapy.
10. The patient has a prior history of GI perforation/fistula (within 6 months of first
dose of protocol therapy) or risk factors for perforation.
11. 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 first dose of protocol therapy. The patient has elective or planned major
surgery to be performed during the course of the clinical trial.
12. The patient is receiving chronic antiplatelet therapy other than aspirin, including
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. Occasional use of NSAIDS is allowed
(occasional use would constitute daily use for less than a week; treating physician
discretion is permitted to differentiate between occasional Vs chronic use).
13. Patients who have not recovered from adverse events due to agents administered earlier
except neuropathy and alopecia. Physician's discretion is allowed to decide which
unresolved adverse events from previous therapy (for NSCLC) prohibit patient
participation in this study.
14. Patients with active autoimmune disease that has required systemic treatment in the
past 1 year (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Hormone replacement therapy (eg. thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment.
15. Patients requiring more than 10mg prednisolone (or its equivalent) per day are
16. Patients with untreated symptomatic brain metastases are excluded. Patients with
treated brain metastases will be allowed if brain imaging obtained within 28 days of
trial enrollment reveals stable disease. Patients with small (<5mm) asymptomatic brain
metastasis are allowed to enroll.
17. Patients with interstitial lung disease or active, noninfectious pneumonitis. Patients
with active tuberculosis infection are excluded.
18. Patient who have received a live vaccine within 30 days prior to Cycle1 Day 1.
19. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia (significant), cirrhosis, or psychiatric illness/social situations that
would limit compliance with study requirements.
20. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS)
21. Known history of chronic hepatitis B virus infection or chronic hepatitis C virus
indicating chronic infection that is not cured.
22. Subjects with previous malignancies (except non-melanoma skin cancers, and in situ
cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma,
or breast) are excluded unless a complete remission was achieved at least 2 years
prior to study entry and no additional therapy is required or anticipated to be
required during the study period.
23. Pregnant or breast-feeding.