| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relpased advanced or metastatic non-small cell lung cancer of adenocarcinoma histology |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025033 |
| E.1.2 | Term | Lung adenocarcinoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064049 |
| E.1.2 | Term | Lung adenocarcinoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025038 |
| E.1.2 | Term | Lung adenocarcinoma stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025037 |
| E.1.2 | Term | Lung adenocarcinoma stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The study is divided into 2 parts: Part 1 is the Phase Ib portion of the trial and Part 2 is the Phase II portion of the trial. Once the Trial Steering Committee has completed the dose limiting toxicity (DLT) assessment for Part 1 and confirmed RP2D for Part 2, Part 2 enrolment will proceed.
The objective(s) for each part are as follows:
Part 1: The objective of Part 1 is to evaluate the safety and tolerability of combination nab-paclitaxel and nintedanib in patients with stage IIIb and IV adenocarcinoma of the lung in second and third treatment line setting and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of nintedanib when given with nab-paclitaxel at 100mg/m2 d1, d8 q21.
Part 2: The primary objective of Part 2 is to explore the efficacy of combination nab-paclitaxel and nintedanib versus nab-paclitaxel and placebo in the same patient population, with nintedanib/placebo given at the recommended phase 2 dose (RP2D) as defined during part 1 of the stu |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives for Part 1:
• To examine the frequency of all adverse events graded by NCI-CTCAE version 4.0.
• To examine the objective tumour response according to RECIST 1.1 criteria (investigator reported), and the overall response rate
•To explore the number of cycles of nab-paclitaxel with nintedanib given
Secondary objectives for Part 2:
• To examine the frequency of all adverse events graded by NCI-CTCAE version 4.0.
• To examine the objective tumour response according to RECIST 1.1 criteria (investigator reported), and the overall response rate.
• To examine overall survival in the intention to treat population and in two predefined subgroups: according to progressive disease before or after 9 months from start of first line systemic therapy; and according to prior or no prior immunotherapy.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria to be enrolled in the study:
1. Male or female patients aged 18 or over.
2. Patients with a pathologically confirmed diagnosis of stage III or stage IV adenocarcinoma of the lung; patients with locally recurrent disease (stage IIIa) and no radical treatment options are also eligible.
3. Patients who have previously received no more than 2 lines of systemic therapy for NSCLC with palliative intent:
i. Chemotherapy as first-line or more with palliative intent
ii. Relapsing within 6 months of adjuvant chemotherapy after surgery or
as part of radical chemo-radiotherapy, which count as one line of therapy.
iii. Licenced or experimental maintenance therapy is allowed (eg.pemetrexed)
iv. Immunotherapy at prior line of treatment (first or second line) is
allowed.
4. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
5. Patients with estimated life expectancy of ≥ 12 weeks.
6. Patients with at least one radiologically measurable tumour lesion as defined by RECIST 1.1 criteria.
7. Patients with adequate haematopoietic, hepatic and renal function.
8. Signed informed consent in accordance with ICH-GCP guidelines and local legislation.
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| E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a patient from enrolment:
1. Patients with a known EGFR kinase sensitising mutation or ALK gene fusion prior to enrolment who have not received prior TKI (patients enrolled and subsequently found to be positive will remain on protocol). Patients with a known EGFR activating mutation or ALK fusion who have received appropriate TKI therapy will be allowed.
2. Any concurrent anticancer systemic therapy.
3. Prior treatment with nintedanib or any other VEGFR inhibitor; prior treatment with bevacizumab is allowed.
4. Patients refractory to prior Taxane therapy for advanced disease. Prior taxane used in the adjuvant setting does not exclude eligibility provided there is no disease recurrence within 12 months upon completion of chemotherapy in that setting.
5. Adequate laboratory parameters defined by:
i. Absolute neutrophil count (ANC) < 1,500/μl (1.5x109/L).
ii. Platelets < 100,000/μl (100x109/L).
iii. Haemoglobin < 9.0 g/dl or requiring transfusions.
iv. Creatinine clearance < 45 ml/min (by local institutional methods).
v. Total bilirubin outside normal limits.
vi. ALT and/or AST > 1.5 x ULN in patients without liver metastasis.
vii. ALT and/or AST > 2.5 x ULN in patients with liver metastasis.
viii. International normalised ratio (INR) > 2, prothrombin time (PT) and partial thromboplastin time (PTT) > 50% of deviation of institutional ULN.
6. Proteinuria CTCAE grade 2 or greater.
7. Pre-existing peripheral sensory neuropathy CTCAE grade 2 or greater.
8. Use of any investigational drug within 4 weeks of randomisation.
9. Radiotherapy within 4 weeks prior to randomisation.
10. Major surgery (other than biopsy) within 4 weeks prior to randomisation.
11. Active brain metastases or leptomeningeal disease (defined as stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least 4 weeks prior to randomisation).
12. Any other active current malignancy (other than non-melanomatous skin cancer, in situ breast or in situ cervical cancer, prostate cancer diagnosed more than 3 years prior, or breast cancer diagnosed more than 5 year prior to randomisation).
13. Active or uncontrolled infections or serious illnesses or medical conditions that in the opinion of the investigator could interfere with the patient’s participation in the study, including:
a. Known active or chronic hepatitis C and/or B infection.
b. Known pre-existing interstitial lung disease.
c. Presence of 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).
d. Gastro-intestinal abnormalities, including inability to take oral medication, requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption, any medical co-morbidity affecting gastrointestinal absorption.
e. History of clinically significant haemorrhagic or thromboembolic event in the past 6 months.
f. Known inherited predisposition to bleeding or thrombosis.
g. Major injuries within the past 10 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.
h. Drug or alcohol abuse.
14. Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of indwelling intravenous device) or anti-platelet therapy (except low dose therapy with acetylsalicylic acid <325mg her day).
15. Radiographic evidence (CT or MRI) of cavitary or necrotic tumours or local invasion of major blood vessels by tumour.
16. Pregnancy or breast feeding; female patients must have a negative pregnancy test (beta-HCG test in urine or serum) prior to commencing study treatment.
17. Patients who are sexually active and unwilling to use a medically acceptable method of contraception during the trial and for at least three months after ceasing study therapy (medically acceptable methods of contraception include total abstinence,permanent steriisation, combined oral, transdermal or intra-vaginal hormonal contraceptives, methoxyprogesterone injections (eg. Depo-provera), copper-banded intra-uterine devices, hormone-impregnated intra-uterine systems and vasectomised partners; all methods of contraception, with the exception of total abstinence, should be used in combination with the use of a condom by male sexual partners).
18. Known hypersensitivity or any contraindications to the trial drugs, including nab-paclitaxel/nintedanib, to their excipients or to contrast media or other ingredients.
19. Patients unable to comply with the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The study is divided into 2 parts. Part 1 is the Phase Ib portion of the trial and Part 2 is the Phase II portion of the trial.
The primary outcome measure of Part 1 is the recommended phase 2 dose (RP2D).
The primary outcome measure of Part 2 is the progression free survival rate at 12 weeks from first dose of nab-paclitaxel and nintedanib or nab-paclitaxel and placebo in relapsed advanced or metastatic adenocarcinoma non-small cell lung cancer.
The progression free survival (PFS) time is measured from first dose of IMP to the date of radiographic documentation of progression (as defined by RECIST v. 1.1) based on investigator assessment, or the date of death due to any cause, whichever is earlier. Patients who have neither progressed nor died will be censored at the day of their last radiographic tumor assessment. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 12 weeks after 1st dose of phase II study treatment |
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| E.5.2 | Secondary end point(s) |
- To evaluate the frequency of all adverse events graded by NCI-CTCAE version 4.0
- To define number of cycles of nintedanib and nab-paclitaxel given
- To evaluate the objective tumour response and overall response rates by RECIST version 1.1
- To explore the overall survival rates by treatment arm in ITT and predefined subgroups by time to progression after start of 1st line treatment and by previous immunotherapy |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description |
| To define the maximum tolerated dose of nintedanib when given in combination with nab-paclitaxel. |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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“End of trial” refers to the date of the last visit or last scheduled procedure for the last patient in the trial.
Study completion is when the scientific evaluation will be complete following the final evaluation of OS, as determined
by the sponsor. Investigators will continue to follow the study schedule for all patients until notified by sponsor that study completion has occurred.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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