This is a multicenter, open-label trial to evaluate the safety, pharmacodynamics (PD),
pharmacokinetics (PK), and efficacy of tomivosertib in combination with paclitaxel in
patients with advanced breast cancer (ABC) of any subtype.
The trial will enroll up to 45 patients with an Eastern Cooperative Oncology Group (ECOG)
performance status (PS) of 0, 1, or 2 with any breast cancer (BC) subtype and at least one
measurable lesion, for whom standard-of-care treatments are ineffective, not tolerated or
All patients will be initially treated with tomivosertib for 14 days (referred as the run-in
period). Once treatment samples are obtained, weekly paclitaxel will be added to the
Tumor assessments will be done at screening and then periodically throughout trial treatment.
Patients will continue to receive trial treatment until progressive disease, as defined
according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1,
intolerable trial-treatment-related toxicity, consent withdrawal, or other criteria is met
(defined within the trial protocol).
1. Signed and dated Patient Informed Consent Form (PICF) obtained prior to any
trial-specific screening procedure.
2. Women or men aged ≥ 18 years-old on the day of the written informed consent is given.
3. Histologically or cytologically confirmed breast adenocarcinoma that is either
metastatic (stage IV of the TNM classification) or locally recurrent and not amenable
to local curative treatment.
4. Known ER, PgR and HER2 statuses (note: the BC subtype at trial entry will be
determined by the statuses in the most recent sample(s) tested for ER, PgR and HER2).
5. Evidence of measurable disease (according to RECIST v.1.1) based on imaging studies
and/or physical examination.
6. Patient is a candidate for weekly paclitaxel as palliative treatment for the locally
recurrent and/or metastatic disease in the opinion of the treating physician, or is
currently receiving paclitaxel (achieving disease control or not). Note: any number of
prior lines of standard-of-care or experimental therapies are allowed.
7. At least one metastatic (or recurrent) lesion that is amenable to repeated biopsy and
willingness and ability to undergo two biopsies (at screening and approximately 2
weeks after the start of trial treatment).
8. ECOG performance status of 0, 1 or 2.
9. Life expectancy of ≥ 6 months per Investigator's judgement.
10. Adequate organ function during screening, as defined below:
- Hemoglobin ≥8.0 g/dL (criterion must be met without erythropoietin dependency and
without packed red blood cell transfusion within the last 2 weeks)
- Absolute neutrophil count ≥1,500 cells/mm3
- Platelet count ≥100,000 cells/mm3
- Total bilirubin ≤1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ULN for
participants with total bilirubin levels >1.5 × ULN
- Aspartate aminotransferase and alanine aminotransferase ≤3 × ULN (≤5 × ULN for
patients with liver metastases)
- Measured or calculated creatinine clearance (CrCl) >60 mL/min (if calculated, it
should be done using the Cockcroft-Gault formula)
11. For women of childbearing potential (WoCBP) - must meet all of the following criteria:
- Not pregnant (negative serum pregnancy within 14 days of enrollment), and
- Not breastfeeding, and
- Willing to use a protocol-recommended method of contraception (refer to details
within protocol), from the start of tomivosertib until at least 30 days after the
last dose of trial treatment.
Note: A female patient is considered to be of childbearing potential unless she has
had a hysterectomy, bilateral tubal ligation/occlusion, or bilateral oophorectomy, has
medically documented ovarian failure (with serum estradiol and follicle-stimulating
hormone levels within the institutional laboratory postmenopausal range), or is
postmenopausal. Post-menopausal status is defined as 12 consecutive months with no
menses without an alternative medical cause.
12. For sexually active male subjects who can father a child - must be willing to refrain
from sperm donation and to use a protocol-recommended method of contraception
(detailed within protocol), from the start of tomivosertib until at least 74 days
after the last dose of trial treatment.
13. Willing and able to comply with the scheduled visits, drug administration plan,
protocol-specified laboratory tests, other trial procedures, and trial restrictions.
Note: psychological, social, familial, or geographical factors that might preclude
adequate trial participation should be considered.
1. Current evidence of incomplete recovery from clinically-significant toxicities
associated with prior anti-cancer treatment(s), that would represent a
contra-indication to experimental therapy in the opinion of the Investigator.
2. Prior systemic standard or investigational anti-cancer therapy within 3 weeks prior to
enrollment and/or major surgery within 2 weeks prior to enrollment.
3. Known symptomatic brain metastases requiring ≥10 mg/day of prednisolone (or its
equivalent). Patients 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, fulfill the steroid requirement
and are neurologically stable.
4. Active infection requiring systemic therapy.
5. Gastrointestinal disease that may interfere with drug absorption or with
interpretation of gastrointestinal adverse events (e.g., gastric or intestinal bypass
surgery, pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic
inflammatory bowel disease, chronic diarrheal illness, bowel obstruction).
6. Significant cardiovascular disease including myocardial infarction, arterial
thromboembolism, or cerebrovascular thromboembolism, within 8 weeks prior to the start
of tomivosertib; unstable dysrhythmias or other known clinically significant
electrocardiogram abnormality; unstable angina; New York Heart Association Class 3 or
4 congestive heart failure; uncontrolled hypertension (diastolic blood pressure ≥100
mmHg and/or systolic blood pressure ≥180 mmHg); or history of congenital prolonged QT
7. Prior therapy with any inhibitor of MNK1 and/or MNK2.
8. Have used a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4, CYP2C9, CYP2D6,
or CYP1A2 within 7 days prior to randomization or are expected to require use of a
strong inhibitor or inducer of CYP3A4, CYP2C9, CYP2D6, or CYP1A2 during study
9. Known or suspected hypersensitivity to the trial drugs or excipients contained in the
10. 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 malignancy
currently in complete remission for ≥2 years.
11. History or current evidence of any other medical or psychiatric condition or addictive
disorder, or laboratory abnormality that, in the opinion of the Investigator, will
increase the risks associated with trial participation, or require treatments that
will interfere with the conduct of the trial or the interpretation of trial results.
12. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or
breast-feed during her trial participation.