PRIMARY OBJECTIVES:
I. To determine the safety of ensartinib in combination with carboplatin, pemetrexed and
bevacizumab in patients with ALK-rearranged advanced non-small cell lung cancer (NSCLC).
II. Determine the recommended phase 2 dose (RP2D) of ensartinib in combination with
carboplatin, pemetrexed and bevacizumab.
SECONDARY OBJECTIVES:
I. To determine an objective response rate (ORR) in patients with ALK-rearranged advanced
NSCLC treated with ensartinib in combination with carboplatin, pemetrexed and bevacizumab
using modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
II. To determine progression-free survival (PFS). III. To determine overall survival.
EXPLORATORY OBJECTIVE:
I. To determine biomarkers associated with response and resistance to the study combination.
OUTLINE: This is a dose de-escalation study of ensartinib and fixed-dose carboplatin,
pemetrexed, and bevacizumab followed by a dose-expansion study.
INDUCTION THERAPY: Patients receive ensartinib orally (PO) once daily (QD) on days 1-21,
carboplatin intravenously (IV) over 15-60 minutes on day 1, pemetrexed IV over 10 minutes on
day 1 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up
to 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive ensartinib PO QD on days 1-21 and bevacizumab IV over
30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Inclusion Criteria:
- Histologically or cytologically confirmed diagnosis of stage IV (metastatic) or
recurrent or stage IIIc NSCLC (recurrent or stage IIIC NSCLC must be not a candidate
for definitive multimodality therapy)
- Documented ALK re-arrangement as detected by: (1) fluorescence in situ hybridization
(FISH), (2) immunohistochemistry (IHC), (3) tissue next generation sequencing (NGS),
or (4) cell free deoxyribonucleic acid (cfDNA) NGS using Clinical Laboratory
Improvement Amendments (CLIA) certified laboratory
- Subjects can be enrolled as (1) treatment naive (2) after progression on any number of
prior ALK tyrosine kinase inhibitors (TKIs). Prior adjuvant platinum-based
chemotherapy and platinum-based chemotherapy for metastatic disease is allowed if
completed > 12 months from the study treatment start date with one exception: a
patient may be eligible if started on chemotherapy while waiting for ALK testing
results, provided no more than two cycles of chemotherapy were administered and no
evidence of disease progression
- Life expectancy of at least 12 weeks
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- Aged at least 18 years
- Brain metastases allowed if asymptomatic at study baseline. Patients must be not on
steroids, with the maximum size of brain lesion not exceeding 30 millimeters. If
patients have neurological symptoms or signs due to central nervous system (CNS)
metastases, patients need to complete whole brain radiation or focal treatment at
least 14 days before start of study treatment and be asymptomatic on stable or
decreasing doses of corticosteroids at baseline
- Ability to swallow and retain oral medications
- Absolute neutrophil count (ANC) >= 1500/mm^3 /L
- Platelet count >= 100,000/mm^3
- Hemoglobin (Hb) at least 9 g/dL (or 5.69 mmol/L) at baseline
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl)
>= 60 mL/minute for subjects with creatinine levels > 1.5 x the institutional ULN
- Serum total bilirubin less than or equal to =< 1.5 x ULN or direct bilirubin =< ULN
for subjects with total bilirubin levels > 1.5 x ULN
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
except for subjects with liver metastases (mets) for whom ALT and AST should be =< 5 x
ULN
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated PTT (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy if
PT or PTT is within therapeutic range of intended use of anticoagulant
- Female patients of childbearing potential must have a negative pregnancy test
documented at time of screening
- Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to use a highly effective method of
contraception from the time of signing the informed consent through 4 months
after the last dose of study drug, or agree to completely abstain from
heterosexual intercourse
- Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
- Agree to practice effective barrier contraception during the entire study
treatment period and through 4 months after the last dose of study drug, or
- Agree to completely abstain from heterosexual intercourse
- Voluntary agreement to provide written informed consent and the willingness and
ability to comply with all aspects of the protocol
Exclusion Criteria:
- Use of an investigational drug within 21 days prior to the first dose of study drug.
Note that to be eligible, any drug-related toxicity should have recovered to grade 2
or less, with the exception of alopecia
- Major surgery within the last 4 weeks or radiotherapy within the last 14 days
- Patients with leptomeningeal disease are ineligible
- Patients with a previous malignancy within the past 2 years (other than curatively
treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, or any
cancer that is considered to be cured and have no impact on PFS and overall survival
[OS] for the current NSCLC)
- Concomitant systemic use of anticancer herbal medications. These should be stopped
prior to study entry
- Patients receiving:
- Strong CYP3A inhibitors (including, but not limited to, atazanavir,
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin, voriconazole, grapefruit, grapefruit juice)
- Strong CYP3A inducers (including, but not limited to, carbamazepine,
phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort)
- CYP3A substrates with narrow therapeutic window (including, but not limited to,
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide,
quinidine, sirolimus, tacrolimus)
- Women who are pregnant or breastfeeding
- Presence of active gastrointestinal (GI) disease or other condition that will
interfere significantly with the absorption, distribution, metabolism, or excretion of
study medications
- Patients at risk for GI perforation
- Clinically significant cardiovascular disease including:
- Corrected QT per Fridericia's formula (QTcF) interval > 450 ms for men and > 470
ms for women, symptomatic bradycardia < 45 beats per minute or other significant
electrocardiogram (ECG) abnormalities in the investigator's opinion
- Clinically uncontrolled hypertension in the investigator's opinion (e.g., blood
pressure > 160/100 mmHg; note that isolated elevated readings considered to not
be indicative of uncontrolled hypertension are allowed)
- The following within 6 months prior to cycle 1 day 1:
- Congestive heart failure (New York Heart class III or IV)
- Arrhythmia or conduction abnormality requiring medication. Note: patients
with atrial fibrillation/flutter controlled by medication and arrhythmias
controlled by pacemakers are eligible
- Severe/unstable angina, coronary artery/peripheral bypass graft, or
myocardial infarction
- Cerebrovascular accident or transient ischemia
- Patients who are immunosuppressed (including known human immunodeficiency virus [HIV]
infection), have a serious active infection at the time of treatment, have
interstitial lung disease/pneumonitis, or have any serious underlying medical
condition that would impair the ability of the patient to receive protocol treatment.
Patients with controlled hepatitis C, in the investigator's opinion, are allowed.
Patients with known hepatitis B must be hepatitis B virus e antigen (HBeAg) and HB
viral deoxyribonucleic acid (DNA) negative for enrollment. Note that, because of the
high prevalence, all patients in the Asia-Pacific region (except Australia, New
Zealand, and Japan) must be tested and, if hepatitis B surface antigen (HBsAg)
positive, must be HBeAg and HB viral DNA negative for enrollment
- Known hypersensitivity to tartrazine, a dye used in the ensartinib 100 mg capsule
- Concurrent condition that in the investigator's opinion would jeopardize compliance
with the protocol or would impart excessive risk associated with study participation
that would make it inappropriate for the patient to be enrolled
- Inability or unwillingness to comply with study and/or follow-up procedures outlined
in the protocol
