This clinical trial is a Phase 1-2, open-label, sequential-group, dose-escalation and
cohort-expansion study evaluating the safety, pharmacokinetics (PK), pharmacodynamics, and
antitumor activity of Zotatifin (eFT226) in subjects with selected advanced solid tumor
malignancies. The study will evaluate weekly 1-hour intravenous (IV) administration of
Zotatifin (eFT226). Treatment and study subject evaluations will be performed in 21 day
Part 1 (dose escalation) will enroll subjects with an advanced solid tumor that is refractory
or intolerant to standard of care therapy, where the tumor is pancreatic adenocarcinoma (no
molecular typing) or any other solid tumor that has a documented activating mutation,
amplification, or fusion of HER2, ERBB3, FGFR1, FGFR2, or an activating mutation in KRAS.
Subjects will be assigned sequentially to increasing eFT226 doses. The starting dose of
eFT226 is 0.005 mg/kg administered IV weekly in 21 day cycles. eFT226 doses will be escalated
in subsequent cohorts after subjects enrolled in a given cohort have completed the 21-day
dose-limiting toxicity (DLT) evaluation period. Dose escalation in Part 1 will enroll
subjects based on 3+3 design, whereby 3 subjects will be initially enrolled and treated at
each dose level.
To obtain as robust a data set as possible regarding PK, safety and tolerability in a diverse
population prior to selecting the RP2D, the MTD and MTD-1 cohorts may be backfilled up to 15
subjects total in each cohort.
Part 2 (Expansion Cohort) of the study will provide cohort expansion to further explore the
safety, pharmacology, and clinical activity of eFT226 monotherapy in subjects with previously
treated advanced solid tumor malignancies. Part 2 will be based on results observed in Part 1
and will be defined by amendment to the protocol.
1. Part 1 (Dose Escalation): Subject has an advanced solid tumor that is refractory or
intolerant to standard of care therapy, where the tumor is pancreatic adenocarcinoma
(no molecular typing required) or any other solid tumor that has at least one of the
following: a documented activating mutation, amplification, or fusion of HER2, ERBB3,
FGFR1, FGFR2, or an activating mutation in KRAS; molecular tumor typing can be
determined by immunohistochemistry (IHC; at IHC2+ or greater level), fluorescence in
situ hybridization (FISH), next generation sequencing, or other analysis methods as
appropriate. If the tumor is breast cancer or gastric cancer, subject must have failed
treatment with trastuzumab as well as another anti-HER2 agent.
2. Men and women of age ≥ 18 years
3. Subject has a life expectancy of 3 months or more.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Has at least 1 measurable lesion per RECIST Version 1.1 criteria.
6. Completion of all previous therapy (including radiotherapy, chemotherapy,
immunotherapy, or investigational therapy) for the treatment of cancer for 4 weeks (6
weeks for nitrosourea or mitomycin) before the start of study therapy.
7. All acute toxic effects of any prior antitumor therapy resolved to Grade 1 before the
start of study therapy (with the exception of alopecia [Grade ≤ 2 permitted],
neurotoxicity [Grade ≤ 2 permitted], or selected laboratory parameters [Grade ≤ 2
permitted with exceptions as noted below])
8. Adequate bone marrow function:
8a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. 8b. Platelet count ≥ 100 × 109/L (Grade
≤ 1). 8c. Hemoglobin ≥ 9.0 g/dL (Grade ≤ 2) maintained for ≥ 2 weeks from any prior
9. Adequate hepatic function during Screening as defined below: 9a. Serum alanine
aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) or ≤5 x ULN if known liver
9b. Serum aspartate aminotransferase (AST) ≤ 3 x ULN or ≤ 5 x ULN if known liver
9c. Serum bilirubin ≤ 1.5 x ULN (unless due to Gilbert's syndrome or hemolysis, in which
case ≤ 3 x ULN is permitted).
10. Adequate renal function: 10a. Measured or estimated creatinine clearance (eClCR) > 50
mL/min (eClCR to be calculated by the Cockcroft-Gault formula 11. Adequate electrolyte
values within 72 hours before the start of study therapy: 11a. Serum potassium within
normal limits (WNL). 11b. Serum calcium (adjusted for serum albumin concentration) WNL.
11c. Serum magnesium WNL. Note: Oral or IV supplementation or medical therapy may be used
to achieve normal values for serum potassium, calcium and magnesium.
12. Adequate coagulation profile: 12a. Prothrombin time (PT) ≤ 1.5 x ULN (Grade ≤ 1). 12b.
Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (Grade ≤ 1).
13. For female subjects of childbearing potential, a negative serum pregnancy test within 7
days prior to start of study therapy.
14. For female subjects of childbearing potential, willingness to use a
protocol-recommended method of contraception from the start of the screening period until ≥
30 days after the final dose of study therapy. Note: A female subject is considered to be
of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and
follicle-stimulating hormone [FSH] levels within the institutional laboratory
postmenopausal range and a negative serum or urine beta human chorionic gonadotropin
[βHCG]); or is menopausal (age ≥ 55 years with amenorrhea for ≥ 6 months).
15. For male subjects who can father a child and are having intercourse with females of
childbearing potential who are not using adequate contraception, willingness to use a
protocol-recommended method of contraception from the start of study therapy until ≥ 30
days after the final dose of study therapy and to refrain from sperm donation from the
start of study therapy until ≥ 90 days after administration of the final dose of study
therapy. Note: A male subject is considered able to father a child unless he has had a
bilateral vasectomy with documented aspermia or a bilateral orchiectomy.
16. In the judgment of the Investigator, participation in the protocol offers an acceptable
benefit-to-risk ratio when considering current disease status, medical condition, and the
potential benefits and risks of alternative treatments for the subject's cancer.
17. Willingness and ability to comply with scheduled visits, drug administration plan,
protocol-specified laboratory tests, other study procedures, and study restrictions.
1. History of another malignancy except for the following: adequately treated local basal
cell or squamous cell carcinoma of the skin; adequately treated carcinoma in situ
without evidence of disease; adequately treated papillary, noninvasive bladder cancer;
other adequately treated Stage 1 or 2 cancers currently in complete remission; or any
other cancer that has been in complete remission for ≥ 2 years.
2. Previously documented or current brain metastases that have not been treated.
3. Significant cardiovascular disease (eg, myocardial infarction, arterial
thromboembolism, cerebrovascular thromboembolism) within 6 months prior to start of
study therapy; symptomatic dysrhythmias or unstable dysrhythmias requiring medical
therapy; unstable angina; symptomatic peripheral vascular disease; New York Heart
Association Class 3 or 4 congestive heart failure; uncontrolled Grade ≥ 3 hypertension
(diastolic blood pressure ≥ 100 mmHg or systolic blood pressure ≥ 160 mmHg) despite
antihypertensive therapy; or history of congenital prolonged QT syndrome.
4. Significant screening ECG abnormalities, including unstable cardiac arrhythmia
requiring medication, left bundle branch block, 2nd degree atrioventricular (AV) block
type II, 3rd degree AV block, Grade ≥ 2 bradycardia, or corrected QT (QTcF) > 450 msec
(based on the average of 3 measurements at 5-minute intervals).
5. Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper
respiratory tract infections) at the time of start of study therapy. Note: Subjects
with localized fungal infections of skin or nails are eligible.
6. Known active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency
virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Note:
Negative Hep B surface antigen and negative Hep B core antibody or undetectable Hep B
virus DNA per qPCR testing; Negative Hep C virus antibody or negative HCV RNA by qPCR
testing; Negative HIV antibody.
7. Pregnancy or breastfeeding.
8. Major surgery within 4 weeks before the start of study therapy or not fully recovered
from major surgery.
9. Prior solid organ transplantation.
10. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids.
Note: At screening, subjects may be using systemic corticosteroids (at doses of ≤ 10
mg of prednisone or equivalent) or topical or inhaled corticosteroids. During study
therapy, subjects may use systemic, enteric, topical or enteric corticosteroids as
required for treatment-emergent conditions.
11. Use of a known QT-prolonging drugs during screening or expected requirement for use
during study therapy
12. Use of a strong or moderate inhibitor or inducer of cytochrome P450 (CYP) 3A4 within 7
days prior to the start of study therapy or expected requirement for use of a strong
or moderate inhibitor or inducer of CYP3A4 during study therapy.
13. Concurrent participation in another therapeutic clinical trial.
14. Any illness, medical condition, organ system dysfunction, or social situation,
including mental illness or substance abuse, deemed by the Investigator to be likely
to interfere with a subject's ability to sign informed consent, adversely affect the
subject's ability to cooperate and participate in the study, or compromise the
interpretation of study results.