| Eligibility |
Inclusion Criteria:
- Written informed consent and any locally-required authorization (EU Data Privacy
Directive in the EU) obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations.
- Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.
- Age over or equal to 18 years at time of study entry.
- Histologically confirmed adenocarcinoma of the lung stage IIIB/IV according to UICC7
- One or two previous lines of systemic therapy including maintenance for advanced or
metastatic NSCLC. Patients should be offered standard therapy regimens as recommended
by current local Clinical Practice Guidelines. Neo-adjuvant and adjuvant therapies are
permitted, provided that disease progression/relapse occurred more than 6 months after
cessation of therapy.
- ECOG performance status 0-1.
- Expected life expectancy of at least 3 months.
- Patients with measurable disease (at least one uni-dimensionally measurable target
lesion by CT-scan or MRI) according to Response Evaluation Criteria in Solid Tumors
(RECIST 1.1) are eligible. If a potential target lesion has been irradiated
previously, clear evidence of progression at target site must be documented.
- A formalin fixed, paraffin-embedded (FFPE) tumor tissue block (archival or recent) or
approx. of 10-15 unstained slides of tumor sample (slices must be recent and collected
on slides provided by the sponsor) must be available for PD-L1 and other biomarker
evaluation. Biopsy should be excisional, incisional or core needle. Fine needle
aspiration is insufficient.
- Prior therapies and surgeries are allowed if completed 2 weeks (for minor surgery) or
4 weeks (palliative radiotherapy for bone pain; major surgeries with complete wound
healing), respectively prior to start of treatment and patient recovered from toxic
effects.
- Adequate blood count, liver-enzymes, and renal function (obtained no later than 14
days prior to start of treatment)
- Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months (30
days plus the time required for nivolumab to undergo five half-lives) after the last
dose of nivolumab. Since the effect of nintedanib on the metabolism and efficacy of
contraceptives has not been investigated, barrier methods should be applied as a
second form of contraception, to avoid pregnancy.
- Women of childbearing potential must have a negative serum or urine pregnancy test
within 24 hours prior to the start of study treatment and monthly throughout treatment
until 5 months after last dose of IMP.
- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 7
months after the last dose of investigational product. Women who are not of
childbearing potential (ie, who are postmenopausal or surgically sterile) as well as
azoospermic men do not require contraception.
Exclusion Criteria:
- More than one or two prior treatment lines for advanced or metastatic NSCLC
- Subjects with active CNS metastases are excluded. Subjects are eligible if CNS
metastases are adequately treated and subjects are neurologically returned to baseline
(except for residual signs or symptoms related to the CNS treatment) for at least 4
weeks prior to enrollment. In addition, subjects must be either off corticosteroids,
or on a stable or decreasing dose of = 10 mg daily prednisone (or equivalent).)
- Leptomeningeal disease, carcinomatous meningitis, chronic diarrhea or short bowel
syndrome
- Known activating EGFR mutation or a known ALK translocation.
- Patients with symptomatic interstitial lung disease.
- Any previous treatment with nitedanib, ramucirumab, anti-tumor vaccines or other
immuno-stimulatory antitumor agents exept checkpoint inhibitors.
- Ongoing toxicities attributed to prior anti-cancer therapy other than alopecia and
fatigue that have not resolved to grade 1 (NCI CTCAE version 4.03) or baseline before
administration of study drug.
- Major injuries 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.
- Patients should be excluded if they have an active, known or suspected autoimmune
disease or history of allogeneic tissue/solid organ transplant. NOTE: Subjects are
permitted to enroll if they have vitiligo, type I diabetes mellitus, residual
hypothyroidism due to autoimmune condition only requiring hormone replacement,
psoriasis not requiring systemic treatment, or conditions not expected to recur in the
absence of an external trigger
- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. NOTE:
Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone
equivalents are permitted in the absence of active autoimmune disease.
- Positive test for HBV sAg or HCV RNA indicating acute or chronic infection OR positive
HIV test
- History of severe hypersensitivity reactions to other monoclonal antibodies or any
excipient. Known hypersensitivity to nintedanib, peanut, soya or to any of the
excipients or contrast media.
- Radiotherapy to the target lesion within the past 3 months prior to baseline imaging.
(see also inclusion criterion 8)
- Radiographic evidence of cavitary or necrotic tumors
- Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of
major blood vessels
- 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 anti-platelet therapy (except for low-dose therapy with acetylsalicylic
acid < 325mg per day)
- 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 12 months prior to start of study treatment,
congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion)
- Active alcohol or drug abuse
- Body Mass Index (BMI) exceeding 20 kg/m2
- Previous malignancy (other than NSCLC), which either progresses or requires active
treatment.
- Subjects with previous malignancies (except non-melanoma skin cancers, and the
following in situ cancers: bladder, gastric, colon, cervical/dysplasia, endometrial,
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.
- Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control
(failure rate of less than 1% per year)
- Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) =28 days prior to the first dose of study
treatment.
- Any other serious or uncontrolled medical disorder (e.g. active ulcers), active
infection, physical exam finding, laboratory finding, altered mental status, or
psychiatric condition that, in the opinion of the investigator, would limit a
subject's ability to comply with the study requirements, substantially increase risk
to the subject, or impact the interpretability of study results.
- Patient who might be dependent on the sponsor, site or the investigator.
- Patient who has been incarcerated or involuntarily institutionalized by court order or
by the authorities ยง 40 Abs. 1 S. 3 Nr. 4 AMG.
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