An Open-label Study Examining the Effect of Tomivosertib (eFT508) in Patients With Advanced Castrate-resistant Prostate Cancer (CRPC)

This Phase 2 study examines the efficacy, safety, tolerability, and pharmacokinetics (PK) of
tomivosertib (eFT508) in advanced CRPC patients who have documented PSA progression on
treatment with apalutamide and/or abiraterone and/or enzalutamide and for whom no suitable
curative therapy exists.

Inclusion Criteria:

- Men ≥18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

- Histologically or cytologically confirmed (by clinical site) adenocarcinoma of the
prostate without neuroendocrine differentiation or small cell features.

- Ongoing androgen deprivation therapy with a GnRH analog or bilateral orchiectomy
(surgical or medical castration).

- Serum testosterone ≤1.73 nmol/L (50 ng/dL) at screening.

- PSA progression on treatment with abiraterone and/or enzalutamide and/or apalutamide.
PSA progression is defined by a minimum of 2 rising PSA levels with an interval of ≥1
week between each determination. PSA value at the screening visit should be ≥2 ng/mL.
Patients may also have:

- Soft tissue disease progression defined by iRECIST/RECIST 1.1

- Bone disease

- Patients receiving bisphosphonate/receptor activator of nuclear factor kappa-Β ligand
(RANKL) therapy must have been on stable doses for ≥ 4 weeks before the start of study
therapy.

- Completion of all previous therapy for the treatment of cancer ≥4 weeks before the
start of study therapy.

- All acute toxic effects of any prior anti-tumor therapy resolved to Grade ≤1 before
the start of study therapy (with the exception of alopecia [Grade 1 or 2 permitted],
neurotoxicity [Grade 1 or 2 permitted], or bone marrow parameters [Grade 1 or 2
permitted with exceptions as noted below]).

- Adequate bone marrow function:

- Absolute neutrophil count (ANC) ≥1.0 x 109/L

- Platelet count ≥75 x 109/L

- Hemoglobin ≥80 g/L (8.0 g/dL or 4.9 mmol/L)

- Adequate hepatic function:

- Serum alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN), ≤ 5 x ULN
in the presence of liver metastases

- Serum aspartate aminotransferase (AST) ≤3 x ULN, ≤5 x ULN in presence of liver
metastases

- Serum bilirubin ≤1.5 x ULN (unless due to Gilbert's syndrome or hemolysis ≤3 x
ULN)

- Adequate renal function:

-Serum creatinine ≤1.5 mg/dL and/or creatinine clearance ≥30 mL/min using Cockcroft
Gault equation (Appendix 13.4)

- For male patients who can father a child and are having intercourse with females of
childbearing potential, willingness to use a protocol-recommended method of
contraception from the start of study therapy and for ≥30 days following the last dose
of study medication or to abstain from sexual intercourse for at least this period of
time, and willingness to refrain from sperm donation from the start of study therapy
to ≥90 days following the last dose of study drug.

- Estimated life expectancy >12 weeks.

- Willingness to comply with scheduled visits, drug administration plan,
protocol-specified laboratory tests and biopsies, other study procedures, and study
restrictions. Note: Psychological, social, familial, or geographical factors that
might preclude adequate study participation should be considered.

- Evidence of a personally signed informed consent indicating that the patient is aware
of the neoplastic nature of the disease and has been informed of the procedures to be
followed, the experimental nature of the therapy, alternatives, potential benefits,
possible side effects, potential risks and discomforts, and other pertinent aspects of
study participation.

Exclusion Criteria:

- History of another malignancy except for the following: adequately treated local basal
cell or squamous cell carcinoma of the skin; 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.

- Rapidly progressive, clinically unstable central nervous system malignancy. Note:
Central nervous system imaging is only required in patients with known or suspected
central nervous system malignancy.

- Significant cardiovascular disease, including myocardial infarction, arterial
thromboembolism, or cerebrovascular thromboembolism within 6 months before the 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; Grade ≥3 hypertension (diastolic
blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg), or history of
congenital prolonged QT syndrome.

- Significant screening electrocardiogram (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
QTcF ≥470 msec.

- Symptomatic or impending cord compression unless appropriately treated beforehand and
clinically stable.

- Patients with gastrointestinal disorders likely to interfere with absorption of study
medication.

- Major surgery within 4 weeks before the start of study therapy.

- Prior treatment with chemotherapy within 3 weeks or at least 4 half-lives, whichever
is longer, before the start of study therapy.

- Prior therapy with any known inhibitor of MNK-1 or MNK-2.

- Treatment with 5-alpha reductase inhibitors within 4 weeks of enrollment.

- Prior flutamide treatment within 4 weeks before the start of study therapy and
evidence of withdrawal response.

- Bicalutamide or nilutamide within 6 weeks before the start of study therapy and
evidence of withdrawal response.

- Enzalutamide or abiraterone or apalutamid within 4 weeks before the start of study
therapy.

a. Steroids given in conjunction with abiraterone must be washed out for at least 2
weeks prior to Cycle 1 Day 1 unless the investigator chooses to maintain at a dose of
≤10 mg/day prednisone or equivalent.

- Use of herbal products that may have hormonal anti-prostate cancer activity and/or are
known to decrease PSA levels (eg, saw palmetto).

- Current use of immunosuppressive medication at the time of randomization, EXCEPT for
the following:

1. intranasal, inhaled, topical steroids, or local steroid injection (eg,
intra-articular injection);

2. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or
equivalent;

3. Steroids as premedication for hypersensitivity reactions (eg, computed tomography
[CT] scan premedication).

- Use of a potent inhibitor or inducer of cytochrome P450 (CYP) 3A4 within 7 days before
the start of study therapy or expected requirement for use of a CYP3A4 inhibitor or
inducer during study therapy (Appendix 13.5).

- Concurrent participation in another therapeutic clinical trial.

- 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 patient's ability to sign informed consent, adversely affect the
patient's ability to cooperate and participate in the study, or compromise the
interpretation of study results.