| Eligibility |
Inclusion Criteria:
- Must provide written informed consent and any authorizations required by local law;
- Men or women 18 years of age;
- Initiated monotherapy with an anti-PD-1 or anti-PD-L1 agent (avelumab, atezolizumab,
durvalumab, nivolumab, or pembrolizumab) in accordance with the package insert, and:
- Are judged by the Principal Investigator as tolerating the anti-PD-1 or anti-PD-L1
therapy, and
- Developed PD per RECIST 1.1 on therapy, or
- Have undergone 12 weeks of anti-PD-1 or anti-PD-L1 therapy with no evidence of PR or
CR;
- ECOG performance status of 0 or 1;
- Has at least 1 measurable lesion per RECIST 1.1 criteria;
- Adequate bone marrow function during Screening as defined below:
- Absolute neutrophil count 1.0 109/L,
- Platelet count 75 109/L, and
- Hemoglobin 80 g/L (8.0 g/dL or 4.9 mmol/L);
- Adequate hepatic function during Screening as defined below:
- Serum alanine aminotransferase 3 upper limit of normal (ULN) or 5 ULN if liver
metastases are present,
- Serum aspartate aminotransferase 3 ULN or 5 ULN if liver metastases are present, and
- Serum bilirubin - total 1.5 ULN (unless due to Gilbert's syndrome or hemolysis);
- Adequate renal function during Screening, defined as measured or estimated creatinine
clearance 60 mL/min calculated by the Cockcroft-Gault formula using actual body
weight;
- Adequate coagulation profile during Screening as defined below:
- Prothrombin time within the ULN, and
- Activated partial thromboplastin time within the ULN;
- Negative antiviral serology during Screening as defined below:
- Negative human immunodeficiency virus antibody,
- Negative hepatitis B surface antigen and negative hepatitis B core antibody or
undetectable hepatitis B virus (HBV) DNA by quantitative polymerase chain reaction
(qPCR) testing. Note: Hepatocellular carcinoma (HCC) subjects with - -- HBV may only
be enrolled if their hepatitis is judged clinically stable by the Investigator, and
- Negative hepatitis C virus (HCV) antibody or negative HCV ribonucleic acid by q PCR.
Note: HCC subjects with HCV are permitted provided they are not being actively
treated;
- Female subjects of childbearing potential must meet all of the following criteria:
- Not pregnant (negative serum pregnancy test during Screening),
- Not breastfeeding, and
- Willing to use a protocol-recommended method of contraception or to abstain from
heterosexual intercourse from the start of Tomivosertib (eFT-508) until at least 30
days after the last dose of Tomivosertib (eFT-508) or anti-PD-1/anti-PD-L1 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
levels within the institutional laboratory postmenopausal range and a negative serum
or urine beta human chorionic gonadotropin); or is menopausal (age 55 years with
amenorrhea for 6 months);
- Male subjects who can father a child must meet all of the following criteria:
- Willing to use a protocol-recommended method of contraception or to abstain from
heterosexual intercourse with females of childbearing potential from the start of
Tomivosertib (eFT-508) until at least 30 days after the last dose of Tomivosertib
(eFT-508) or anti-PD-1/anti-PD-L1 therapy, and
- Willing to refrain from sperm donation from the start of Tomivosertib (eFT-508) until
at least 90 days after the last dose of Tomivosertib (eFT-508) or anti-PD-1/anti-PD-L1
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;
- Willing to comply with the scheduled visits, drug administration plan,
protocol-specified laboratory tests, other study procedures, and study restrictions.
Note: Psychological, social, familial, or geographical factors that might preclude
adequate study participation should be considered;
- 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; and
- Estimated life expectancy of 3 months.
Exclusion Criteria:
- Currently in CR or PR with anti-PD-1 or anti-PD-L1 monotherapy (avelumab,
atezolizumab, durvalumab, nivolumab, or pembrolizumab);
- History of another malignancy except for the following: adequately treated local basal
cell or squamous cell carcinoma of the skin; in situ cervical carcinoma; 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
- Gastrointestinal (GI) disease (eg, gastric or intestinal bypass surgery, pancreatic
enzyme insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease,
chronic diarrheal illness, bowel obstruction) that may interfere with drug absorption
or with interpretation of GI AEs;
- Known symptomatic brain metastases requiring 10 mg/day of prednisolone (or its
equivalent). Subjects with previously diagnosed brain metastases are eligible if they
have completed their treatment, have recovered from the acute effects of radiation
therapy or surgery prior to the start of Tomivosertib (eFT-508), fulfill the steroid
requirement for these metastases, and are neurologically stable;
- Significant cardiovascular disease, including myocardial infarction, arterial
thromboembolism, or cerebrovascular thromboembolism, within 6 months prior to start of
Tomivosertib (eFT-508); symptomatic dysrhythmias or unstable dysrhythmias requiring
medical therapy; angina requiring therapy; symptomatic peripheral vascular disease;
New York Heart Association Class 3 or 4 congestive heart failure; Grade 3 hypertension
(diastolic blood pressure 100 mmHg or systolic blood pressure 160 mmHg); or history of
congenital prolonged QT syndrome;
- Significant ECG abnormalities at Screening, including unstable cardiac arrhythmia
requiring medication, left bundle branch block, second-degree atrioventricular (AV)
block type II, third-degree AV block, Grade 2 bradycardia, or QT interval corrected
using Fridericia's formula >450 msec (for men) or >470 msec (for women);
- Ongoing risk for bleeding due to active peptic ulcer disease or bleeding diathesis;
- Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper
respiratory tract infections) at the start of Tomivosertib (eFT-508). Note: Subjects
with localized fungal infections of skin or nails are eligible. Subjects may be
receiving prophylactic antibiotics as long as the antibiotic is not prohibited by the
protocol due to the potential for drug-drug interactions;
- Has received a live vaccine within 30 days of planned start of Tomivosertib (eFT-508);
- Pregnant or breastfeeding;
- Major surgery within 4 weeks before the start of Tomivosertib (eFT-508);
- Prior solid organ or bone marrow progenitor cell transplantation;
- Prior therapy with any known inhibitor of MNK1 or MNK2;
- Prior high-dose chemotherapy requiring stem cell rescue;
- History of or active autoimmune disorders or other conditions that might impair or
compromise the immune system;
- Any prior exposure to cytotoxic T-lymphocyte-associated protein 4 inhibitors;
- Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids.
Note: At Screening and during study participation, subjects may be using systemic
corticosteroids (doses 10 mg of prednisone or equivalent) or topical or inhaled
corticosteroids;
- Use of a strong inhibitor or inducer of cytochrome P450 (CYP)3A4 within 7 days prior
to the start of Tomivosertib (eFT-508) or expected requirement for use of a strong
CYP3A4 inhibitor or inducer during study participation; Need for proton pump
inhibitors and histamine H2 blockers at study entry;
- Previously received investigational product in a clinical trial within 30 days or
within 5 elimination half-lives (whichever is longer) prior to the start of
Tomivosertib (eFT-508), or is planning to take part in another clinical trial while
participating in this study;
- Has 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 Document(s),
adversely affect the subject's ability to cooperate and participate in the study, or
compromise the interpretation of study results;
- Portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac -
involvement of HCC based on imaging; or
- Has had esophageal or gastric variceal bleeding within the last 6 months.
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