PRIMARY OBJECTIVES:
I. Determine the recommended phase II dose (RP2D) of osimertinib and necitumumab in
combination with trastuzumab. (Phase Ib) II. Evaluate the efficacy of osimertinib,
necitumumab, and trastuzumab (ONT) as measured by objective response rate (ORR), which is
defined as complete response (CR) or partial response (PR) by Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1. (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate the efficacy of ONT as measured progression free survival (PFS), duration of
response (DoR), and overall survival (OS).
II. To evaluate the safety and tolerability of ONT as measured by adverse events (AEs)
defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V 5.0).
EXPLORATORY OBJECTIVES:
I. To assess patient-reported outcomes on health-related quality of life and adverse events.
II. Assess potential biomarkers associated with response from liquid biopsies and optional
but recommended baseline tissue biopsy.
IIa. Correlate pre-and post-treatment biopsies molecular changes with response. III.
Correlate mutant allele fraction in circulating tumor deoxyribonucleic acid (DNA) (ctDNA) via
liquid biopsy with response.
OUTLINE: This is a phase Ib, dose-escalation study of osimertinib and necitumumab followed by
a phase II study.
Patients receive necitumumab intravenously (IV) over 60 minutes and trastuzumab IV over 30-90
minutes on days 1 and 15. Patients also receive osimertinib orally (PO) once daily (QD) on
days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
After the completion of study treatment, patients are followed up at 30 days, every 8 weeks
through week 24, then every 12 weeks up to 1 year.
Inclusion Criteria:
- Willing and able to provide informed consent
- Cytologically or histologically confirmed non-small cell lung cancer (NSCLC), that is
stage IV (metastatic), with an activating and sensitizing EGFR mutation (e.g., exon 20
insertion mutations are excluded). Enrollment of patients with mutations other than
exon 19 deletion and the L858R point mutation require literature supporting
sensitivity to EGFR tyrosine kinase inhibitors
- Progressed on osimertinib. Osimertinib must have been included as the last systemic
therapy prior to trial enrollment. This excludes patients who received osimertinib in
combination with other EGFR-tyrosine kinase inhibitor (TKI) or anti-human epidermal
growth factor receptor (anti-HER) therapy
- Measurable disease, as per RECIST 1.1
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Able to swallow the study drugs, has no known intolerance of study drugs or
excipients, and able to comply with study requirements
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance >= 50 mL/min for participants with creatinine levels > 1.5 X
institutional ULN (Glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl])
- Creatinine clearance may be calculated following institutional practices
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN.
- If a patient experiences elevated alanine aminotransferase (ALT) > 5 X ULN and
elevated total bilirubin > 2 X ULN, clinical and laboratory monitoring should be
initiated by the investigator. For patients entering the study with ALT > 3 X
ULN, monitoring should be triggered at ALT > 2 X baseline
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
ALT (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for
participants with liver metastases.
- If a patient experiences elevated ALT > 5 X ULN and elevated total bilirubin > 2
X ULN, clinical and laboratory monitoring should be initiated by the
investigator. For patients entering the study with ALT > 3 X ULN, monitoring
should be triggered at ALT > 2 X baseline
- Albumin >= 2.5 g/dL.
- International Normalized Ratio (INR) or Prothrombin Time (PT), and activated partial
thromboplastin Time (aPTT) =< 1.5 X ULN unless participant is receiving anticoagulant
therapy, and then only as long as PT or PTT is within therapeutic range of intended
use of anticoagulants
- Left ventricular ejection fraction >= 50% as measured by transthoracic or
transesophageal echocardiogram within 60 days prior to receiving study treatment
- Female participants of childbearing potential must have a negative urine or serum
pregnancy test. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required. The serum pregnancy test must be negative for
the participant to be eligible, and the participant must agree to use two
highly-effective methods of birth control from the time of the first study drug
treatment through 180 days after the last study drug treatment, or be of
non-childbearing potential. Non-childbearing potential is defined as follows (by other
than medical reasons):
- >= 45 years of age and has not had menses for > 2 years,
- Participants who have been amenorrhoeic for < 2 years without history of a
hysterectomy and oophorectomy must have a follicle stimulating hormone value in
the postmenopausal range upon screening evaluation, or
- Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation
- Male participants must use a condom when having sex with a pregnant woman and when
having sex with a woman of childbearing potential from the time of the first
study-drug treatment through 180 days after the last study drug treatment.
Contraception should be considered for a non-pregnant female partner of childbearing
potential
- Male and female participants must agree not to donate sperm or eggs, respectively,
from the first study-drug treatment through 180 days after the last study drug
treatment
- Female participants must agree to not breastfeed during the study or for 180 days
after the last dose of study treatment
- Participants must agree to not donate blood during the study or for 90 days after the
last dose of study treatment
Exclusion Criteria:
- Concurrent enrollment in another clinical study, unless enrolled only in the follow-up
period or an observational study
- Any chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment in
the prior 3 weeks, other than osimertinib. Concurrent use of hormones for
non-cancer-related conditions (eg, insulin for diabetes and hormone replacement
therapy) is acceptable. Stereotactic, palliative radiation for symptomatic bone
metastases is acceptable without a washout. Stereotactic brain radiation for
asymptomatic brain metastases is acceptable with a 7 day washout
- Use of any investigational anticancer therapy received within 28 days prior to the
first dose of study drugs
- Prior treatment with the combination of two or more of the following therapies which
target EGFR/HER: osimertinib (Tagrisso), erlotinib (Tarceva), gefitinib (Iressa),
afatinib (Gilotrif), lapatinib (Tykerb), neratinib (Nerlynx), vandetanib (Caprelsa),
cetuximab (Erbitux), trastuzumab (Herceptin), pertuzumab (Perjeta), ado-trastuzumab
emtansine (Kadcyla), panitumumab (Vectibix), necitumumab (Portrazza), dacomitinib
(Vizimpro), poziotinib, or other combination deemed as "combined HER-inhibition
therapy" by the investigator
- Has not recovered (recovery is defined as National Cancer Institute [NC] Common
Terminology Criteria for Adverse Events [CTCAE v5.0] grade =< 1) from the acute
toxicities of previous therapy, except treatment-related alopecia, sensory neuropathy,
or laboratory abnormalities otherwise meeting the inclusion requirements stated in the
inclusion criterion. Other grade 2 or less toxicities not constituting a safety risk
based on the investigator's judgment are acceptable
- Known small cell lung cancer or small cell transformation
- The patient has a known allergy / history of hypersensitivity reaction to any of the
treatment components or any other contraindication to one of the administered
treatments
- History or evidence of current clinically relevant coronary artery disease >= grade
III by the Canadian Cardiovascular Society Angina Grading Scale or uncontrolled
congestive heart failure of current >= class III as defined by the New York Heart
Association, or unstable cardiac arrhythmia requiring medication (atrial fibrillation
is permitted if clinically stable)
- The patient has experienced myocardial infarction within 6 months prior to study
enrollment
- The patient has any ongoing or active infection, including active tuberculosis or
known infection with the human immunodeficiency virus, or active, clinically
significant infection requiring the use of parenteral anti-microbial agents, or grade
> 2 by NCI CTCAE (v5.0) within 14 days prior to enrollment
- The patient is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the trial, starting with the screening visit through
180 days after the last dose of trial treatment
- Progressive or symptomatic brain metastases. Brain metastases that have been radiated,
are asymptomatic, and on a stable or decreasing dose of steroids are allowed.
Leptomeningeal disease is excluded
- Serious accompanying disorder or impaired organ function, including major surgery
within 3 weeks before randomization
- Requirement for IV alimentation (at the time of enrollment)
- History of another cancer within 2 years of study initiation, with the exception of
fully treated cancers unlikely to affect the assessment of the study treatment safety
or efficacy including early stage breast, prostate, non-melanomatous skin, thyroid,
cervical, or endometrial cancer
- Gastrointestinal disorder affecting absorption
- Participants must not be considered a poor medical risk due to a serious, uncontrolled
medical disorder, nonmalignant systemic disease, or active, uncontrolled infection.
Examples include, but are not limited to, uncontrolled ventricular arrhythmia,
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena
cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent
- Patient unwilling or unable to comply with the protocol
- Any condition that, in the opinion of the investigator or sponsor, would interfere
with evaluation of the investigational product or interpretation of subject safety or
study results
- History of arterial or venous thromboembolism within 3 months prior to study
enrollment. Patients with a history of venous thromboembolism beyond 3 months prior to
study enrollment can be enrolled if they are appropriately anticoagulated
- Recent (within 30 days before enrollment) or concurrent yellow fever vaccination
