Non-Small Cell Lung Cancer

Study I4T-MC-JVDL is an open-label, multicenter Phase 1 study with expansion cohorts to evaluate the safety andpreliminary efficacy of ramucirumab or necitumumab in combination with osimertinib. The dose-limiting toxicity(DLT) observation period and expansion cohorts (safety and preliminary efficacy) will include patients withadvanced T790M-positive epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer afterprogression on first-line EGFR tyrosine kinase inhibitor therapy.

Ramucirumab, Necitumumab, Osimertinib

Necitumumab
Osimertinib( TAGRISSO)
Ramucirumab(Cyramza)

Injection
Injection
Oral

500mg/50mL
800mg/50mL
80mg

Primary Outcome Measures :
Number of Participants with Dose Limiting Toxicities (DLTs) [ Time Frame: Up to Two Cycles (Up to 21 Day Cycles) ]

Secondary Outcome Measures :
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab [ Time Frame: Day 1 Cycle 2 to Day 1 Cycle 13 (14 Day Cycles) ]
PK: Cmin of Necitumumab [ Time Frame: Day 1 Cycle 3 to Day 1 Cycle 9 (21 Day Cycles) ]
Objective Response Rate (ORR): Percentage of Participants with a Complete Response (CR) or Partial Response (PR) [ Time Frame: Baseline to Objective Disease Progression (Approximately 30 Months) ]
Disease Control Rate (DCR): Percentage of Participants with CR, PR or Stable Disease (SD) [ Time Frame: Baseline to Objective Disease Progression (Approximately 30 Months) ]
Duration of Response (DoR) [ Time Frame: Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Approximately 30 Months) ]
Progression Free Survival (PFS) [ Time Frame: Baseline to Measured Progressive Disease or Death from Any Cause (Approximately 30 Months) ]
Overall Survival (OS) [ Time Frame: Baseline to Death from Any Cause (Approximately 30 Months) ]

Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] Have a diagnosis of NSCLC with at least 1 measurable lesion assessable using
standard techniques by the Response Evaluation Criteria In Solid Tumors
Version 1.1 (RECIST 1.1; Eisenhauer et al. 2009)
[2] Have locally advanced or metastatic NSCLC not amenable to curative therapy
[3] Have lung cancer with documented evidence of one of the 2 common EGFR
mutations known to be associated with EGFR TKI sensitivity (Ex19del,
L858R)
[4] Have disease progression immediately following first-line EGFR TKI
treatment (with disease control as the best response to the first-line EGFR TKI
treatment) regardless of prior chemotherapy
[5] Have T790M-positive status using a test validated and performed locally after
disease progression on EGFR TKI treatment
[6] Tumor tissue from a biopsy taken after disease progression on the most recent
EGFR TKI treatment is required. Patients for whom newly obtained samples
cannot be obtained (for example, inaccessible or patient safety concern) may
submit an archived specimen only upon agreement from the Sponsor.
[7] Have Eastern Cooperative Oncology Group Performance Status of 0 or 1 at
the time of enrollment (Oken et al. 1982)
[8] Have provided signed informed consent and are amenable to compliance with
protocol schedules and testing
[9] Have serum albumin that is ≥25 g/L at the time of enrollment
[10] Have urinary protein that is <2+ on dipstick or routine urinalysis. If urine
dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour urine
must be collected and must demonstrate <2 g of protein in 24 hours to allow
participation in the study.
[11] Have adequate organ function, as defined below, with all screening labs
performed within 7 days of treatment initiation:
[12] Be at least 18 years old at the time of signing informed consent
[13] Have a life expectancy of ≥3 months
[14] Have resolution, except where otherwise stated in the inclusion criteria, of all
clinically significant toxic effects of prior systemic cancer therapy, surgery, or
radiotherapy to Grade ≤1 by NCI CTCAE Version 4.0
[15] For male patients, are sterile (including vasectomy confirmed by
postvasectomy semen analysis) or agree to use a highly effective method of
contraception (2 methods preferred), and to not donate sperm starting with the
first dose of study therapy, during the study, and for at least 6 months
following the last dose of study therapy or country requirements, whichever is
longer. Refer to Appendix 1 for definition of highly effective method of
contraception.
[16] For female patients, are surgically sterile, postmenopausal (see Section 6.3.2
in detail), or agree to use a highly effective method of contraception (2
methods preferred) during the study, and for 6 months following the last dose
of study treatment or country requirements, whichever is longer. Refer to
Appendix 1 for definition of highly effective method of contraception.
[17] For female patients and of child-bearing potential, must have a negative serum
or urine pregnancy test within 7 days prior to enrollment, and should not be
breast feeding
Note: Non-childbearing potential (by other than medical reasons) is defined
in Section 6.3.2.

Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[18] Previous treatment with an EGFR mAb (except for past treatment for
squamous cell carcinoma of head and neck or mCRC)
[19] Previous treatment with an EGFR TKI (for example, erlotinib or gefitinib)
within 8 days or approximately 5x half-life, whichever is longer, of the first
dose of study treatment (If sufficient wash-out time has not occurred due to
schedule or PK properties, an alternative appropriate wash-out time based on
known duration and time to reversibility of drug-related AEs could be agreed
upon by the Sponsor and the investigator.)
[20] Previous treatment with osimertinib or other third-generation EGFR TKIs
[21] Patients with symptomatic or growing brain metastases less than 4 weeks
prior to enrollment. Patients with asymptomatic and stable brain metastases,
such as those who have completed radiotherapy for brain metastases at least
4 weeks prior to receiving treatment and requiring no steroids or
anticonvulsants for at least 2 weeks prior to receiving treatment, are eligible.
[22] Have a serious concomitant illness or medical condition(s) including, but not
limited to, the following:
 Active infection including hepatitis B, hepatitis C, and human
immunodeficiency virus (HIV) infection. Screening for chronic conditions
is not required.
 Active or uncontrolled clinically serious infection
 Active substance abuse disorders
 History of drug-induced interstitial lung disease (ILD), ILD, or radiation
pneumonitis requiring treatment with steroid prior to study enrollment, or
any evidence of clinically active ILD
 Known allergy or hypersensitivity reaction to any of the treatment
components
[23] Have history of another malignancy in 3 years, EXCEPT:
 adequately treated nonmelanomatous skin cancer,
 curatively treated cervical carcinoma in situ,
 other noninvasive carcinoma or in situ neoplasm, or
 prostate cancer that is not expected to impact patient survival
[24] Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding
episode within 12 weeks prior to enrollment. Patients with a history of gross
hemoptysis (defined as bright red blood of ≥1/2 teaspoon) within 2 month
prior to enrollment are excluded.
[25] Have experienced any arterial thrombotic event or arterial thromboembolic
event, including myocardial infarction, unstable angina (history or evidence of
current clinically relevant coronary artery disease of current ≥Class III as
defined by Canadian Cardiovascular Society Angina Grading Scale
[Campeau 1976] or congestive heart failure of current ≥Class III as defined by
the New York Heart Association), cerebrovascular accident, or transient
ischemic attack, within 6 months prior to enrollment
[26] Have a history of deep vein thrombosis, pulmonary embolism, or any other
significant venous thromboembolism (venous catheter thrombosis or
superficial venous thrombosis not considered “significant”) during the
3 months prior to study enrollment. Patients with venous thromboembolism
occurring 3 to 6 months prior to study enrollment are allowed, if being treated
with low molecular weight heparin.
[27] Have a history of GI perforation and/or fistula within 6 months prior to
enrollment
[28] Have a bowel obstruction, history or presence of inflammatory enteropathy or
extensive intestinal resection (hemicolectomy or extensive small intestine
resection with chronic diarrhea), Crohn’s disease, ulcerative colitis, or chronic
diarrhea
[29] Have uncontrolled hypertension, as defined in CTCAE Version 4.0, prior to
initiating study treatment, despite antihypertensive intervention. CTCAE
Version 4.0 defines uncontrolled hypertension as Grade >2 hypertension;
clinically, the patient continues to experience elevated blood pressure (systolic
>160 mmHg and/or diastolic >100 mmHg) despite medications.
[30] Are receiving chronic therapy with any of the following medications within
7 days prior to enrollment:
a. nonsteroidal anti-inflammatory agents (NSAIDs; such as indomethacin,
ibuprofen, naproxen, or similar agents)
b. other antiplatelet agents (such as clopidogrel, ticlopidine, dipyridamole, or
anagrelide)
Aspirin use at doses up to 325 mg/day is permitted.
[31] Have had a serious or non-healing wound, ulcer, or bone fracture within
28 days prior to enrollment
[32] Have an elective or a planned major surgery during the course of the trial
[33] Have undergone major surgery within 28 days prior to enrollment, or minor
surgical procedure such as central venous access device placement within
7 days prior to enrollment
[34] Are currently enrolled in, or discontinued within the last 30 days from, a
clinical trial involving an investigational product or any other type of medical
research judged not to be scientifically or medically compatible with this
study (except in the setting of EGFR TKI as detailed above). Patients
participating in surveys or observational studies are eligible to participate in
this study.
[35] Are pregnant, or breastfeeding
[36] Have radiologically documented evidence of major blood vessel invasion or
encasement by cancer
[37] Have radiographic evidence of pulmonary intratumor cavitation, regardless of
tumor histology
[38] Are receiving concurrent treatment with other anticancer therapy, including
other chemotherapy, immunotherapy, hormonal therapy, chemoembolization,
or targeted therapy or radiotherapy treatment to more than 30% of the bone
marrow or with a wide field of radiation within 4 weeks prior to enrollment
(except in the setting of EGFR TKI as detailed above).
[39] Are currently receiving (or unable to stop use at least 1 week prior to
receiving the first dose of osimertinib) medications or herbal supplements
known to be potent inducers of CYP3A4 (refer to Appendix 7).
[40] Have any of the following cardiac abnormal findings:
 Mean resting corrected QT interval (QTc) >470 msec obtained from
3 electrocardiograms (ECGs), using the screening clinic ECG
machine-derived QTc value
 Any clinically important abnormalities in rhythm, conduction, or
morphology of resting ECG; for example, complete left bundle branch
block, third-degree heart block, or second-degree heart block
 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 interval
 Have a history of any of the following conditions: presyncope or syncope
of either unexplained or cardiovascular etiology, ventricular arrhythmia
(including but not limited to ventricular tachycardia and ventricular
fibrillation), or sudden cardiac arrest
[41] Have undergone chest irradiation within 2 weeks prior to study drug
administration, have not recovered from all radiation-related toxicities, or
requires corticosteroids. A 2-week washout is permitted for focal palliative
radiation to non-central nervous system disease.
[42] Have refractory nausea and vomiting, inability to swallow the formulated
product, or previous significant bowel resection that would preclude
absorption
[43] Have any other serious uncontrolled medical disorders or psychological
conditions that would, in the opinion of the investigator, limit the patient’s
ability to complete the study or sign an informed consent document
[44] Have liver cirrhosis at a level of Child-Pugh B (or worse) or liver cirrhosis
(any degree) and a history of hepatic encephalopathy or clinical meaningful
ascites resulting from cirrhosis