| Eligibility |
Inclusion Criteria:
- Participants must have histologic or cytological diagnosis of advanced/metastatic
Non-Small Cell Lung Cancer (NSCLC) with no curative treatment options. For those with
mixed histology, there must be a predominant histology.
- 18 years of age or older on day of signing informed consent.
- Life expectancy of at least 3-6 months.
- Eastern Cooperative Oncology Group (ECOG) performance status score 0 and 1
- For phase I trial portion, treatment naïve or patients previously treated with
chemotherapy, immunotherapy or targeted therapy for NSCLC are allowed. Patient who
underwent curative intent chemotherapy and/radiation in the neoadjuvant or adjuvant
setting are allowed to enroll if tumor recurrence occurred greater than 6 months from
completion of that therapy (and will be considered treatment naïve in the Stage IV
setting). Patients with NSCLC tumor known to harbor a genomic aberration for which FDA
approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M
mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to
enroll if they have received prior treatment with the FDA approved targeted therapy.
- For phase II trial portion, Patients will be enrolled as two parallel cohorts:
- A.) Arm A (treatment naïve): Patients who are newly diagnosed and treatment
naïve. Patient who underwent curative intent chemotherapy and/radiation in the
neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence
occurred greater than 6 months from completion of therapy. Patients with NSCLC
tumor known to harbor a genomic aberration for which FDA approved treatment is
available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK
rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if
they have received prior treatment with the FDA approved targeted therapy.
- B.) Arm B (Immunotherapy pre-treated group): Patients who have received prior
immunotherapy. Patients who are primary refractory to immunotherapy (i.e.,
Patients who were previously treated with immunotherapy and did not at least
achieve stable disease on first imaging assessment on immunotherapy) or have
relapsed disease (i.e., Patients that were treated with immunotherapy, achieved
at least stable disease on first imaging assessment and subsequently developed
disease progression or relapse). Patients with NSCLC tumor known to harbor a
genomic aberration for which FDA approved treatment is available (i.e,
non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS
rearrangement, BRAF V600E mutation) are allowed to enroll if they have received
prior treatment with the FDA approved targeted therapy
- At least one measurable lesion according to Response Evaluation Criteria in Solid
Tumors (RECIST) v1.1 criteria.
- QTcB must be <470 ms for males and <480 ms for females.
- Adequate normal organ and marrow function as defined below:
- Absolute neutrophil count (ANC) >1.5 x 10^9/L (> 1500 per mm^3)
- Hemoglobin = 9.0 g/dL
- Platelet count = 100 x 10^9/L (>100,000 per mm^3)
- Total bilirubin = 1.5 X normal institutional limits. For patients with liver
metastasis: total bilirubin must be within normal limits.
- Proteinuria less than Common Terminology Criteria for Adverse Events (CTCAE)
grade 2 or greater
- (Except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL
- AST (SGOT)/ALT(SGPT) =1.5 X institutional upper limit of norma (ULN)l or = 2.5 X
ULN for patients with liver metastases. This will not apply to patients with
confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is
predominantly unconjugated in the absence of hemolysis or hepatic pathology), who
will be allowed only in consultation with their physician.
- Serum creatinine CL = 1.5 X ULN or creatinine clearance > 45 mL/min by the
Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection
for determination of creatinine clearance.
- Have archival tissue where available.
- In addition, patients enrolled on the clinical trial must be willing and able to
provide tissue from a newly obtained core or excisional biopsy of a tumor lesion.
Patients for whom newly obtained samples cannot be provided may submit an archived
specimen only upon agreement from the Sponsor.
- Female participants of childbearing potential should have a negative urine or serum
pregnancy within 72 hours before receiving the first dose of study medication. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required.
- Ability to understand and willingness to provide written informed consent signed and
dated prior to admission to the study in accordance with International Conference on
Harmonisation-Good Clinical Practice (ICH-GCP) guidelines and to the local
legislation.
Exclusion Criteria:
- Concurrent use of other anticancer agents including chemotherapy, targeted therapy,
radiotherapy or immunotherapy not otherwise specified in the protocol.
- Concurrent use of other investigational drugs or treatment in another clinical trial
with a non- FDA-approved medication within the past 4 weeks before start of therapy.
- Chemo-, or immunotherapy or therapy with monoclonal antibodies or small tyrosine
kinase inhibitors within the past 2 weeks prior to treatment with the trial drug.
- Radiotherapy (except for brain and extremities or stereotactic treatment) within the
past 2 weeks prior to treatment with the trial drug.
- In immunotherapy pretreated patients, any history of dose-limiting toxicity with prior
immunotherapy agents, including grade 3/4 immune-related adverse events (irAEs);
irreversible irAEs; Grade =3 irAEs that did not respond to steroid rescue; or
neurologic irAE with significant clinical sequelae.
- Prior treatment with nintedanib (BIBF1120).
- Known hypersensitivity to nintedanib, nivolumab, ipilimumab, peanut or soy or any
other trial drug, or their excipients.
- Any toxicity (>CTCAE version 5 grade 3) from previous anti-cancer therapy that has not
resolved to a Grade 1. Persistence of clinically relevant therapy related toxicity
from previous chemo and/or radiotherapy. Patients with irreversible toxicity that is
not reasonably expected to be exacerbated by the investigational product may be
included (e.g., hearing loss, peripherally neuropathy, alopecia).
- History of leptomeningeal carcinomatosis.
- Radiotherapy to a target lesion within the past 3 months prior to baseline imaging
unless that area has demonstrated progression.
- Active brain metastases (e.g., stable for <2 weeks, symptomatic, no adequate previous
treatment, requiring treatment with anti-convulsants); dexamethasone therapy will be
allowed if administered as stable or decreasing dose for at least 3 weeks before
randomization otherwise no steroids to exceed prednisone 10 mg/day prior to starting
trial treatment. Symptomatic or uncontrolled central nervous system (CNS) metastasis.
- Current or prior use of immunosuppressive medication 7 days before the first dose of
nivolumab or ipilimumab, with the exceptions of intranasal and inhaled corticosteroids
or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day
of prednisone, or an equivalent corticosteroid. A brief course (=28 days) of
corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of
non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by
contact allergen) is permitted. Topical corticosteroids are permitted.
- Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients
with vitiligo, Grave's disease, type I diabetes mellitus or residual hypothyroidism
due to autoimmune condition only requiring hormone replacement, or psoriasis not
requiring systemic treatment (within the past 2 years) are not excluded.
- Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of
major blood vessels.
- Has known history of, or any evidence of active, non-infectious pneumonitis.
- Therapeutic anticoagulation with drugs requiring INR monitoring (except low-dose
heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous
devise) or antiplatelet therapy (except for low-dose therapy with acetylsalicylic acid
< 325 mg per day.
- Major injuries and/or surgery within the past 4 weeks prior to start of study
treatment with incomplete wound healing and/or planned surgery during the on-treatment
study period.
- History of clinically significant hemorrhagic or thromboembolic event in the past 6
months.
- Known inherited predisposition to bleeding or thrombosis.
- Significant cardiovascular diseases (i.e., uncontrolled hypertension, unstable angina,
history of infarction within the past 3 months prior to start of study treatment,
congestive heart failure > New York Heart Association (NYHA) II, serious cardiac
arrhythmia).
- Coagulation parameters: International normalized ratio (INR) > 2, prothrombin time
(PT) and partial thromboplastin time (PTT) > 50% of deviation of institutional ULN.
- History of another primary malignancy within the past 2 years except for:
- Basal cell skin cancer
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease (e.g., cervical
cancer in situ)
- Active serious infections in particular if requiring systemic antibiotic or
antimicrobial therapy
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected)
- History of known active primary immunodeficiency
- History of allogeneic organ transplant
- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving study treatment.
- Gastrointestinal disorders or abnormalities that would interfere with absorption of
the study drug
- Serious illness or concomitant non-oncological disease such as neurologic,
psychiatric, infectious disease or active ulcers (gastrointestinal tract, skin) or
laboratory abnormality that may increase the risk associated with study participation
or study drug administration and in the judgment of the investigator would make the
patient inappropriate for entry into the study
- Patients who are sexually active and unwilling to use a medically acceptable method of
contraception (e.g., such as implants, injectables, combined oral contraceptives, some
intrauterine devices or vasectomized partner for participating females, condoms for
participating males) for the duration specified during the trial and after end of
active therapy
- Pregnancy or breastfeeding female patients must have a negative pregnancy test (ß-HCG
test in urine or serum) prior to commencing study treatment
- Psychological, familial, sociological, or geographical factors potentially hampering
compliance with the study protocol and follow-up schedule
- Active alcohol or drug abuse
- Significant weight loss (> 20% of Body Weight) within past 6 months prior to inclusion
into the trial
- History of active tuberculosis
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