Clinical trial NCT03690141
Conditions: Castrate-resistant Prostate Cancer (CRPC)
Keywords: Prostate Cancer Castrate-resistant Prostate Cancer CRPC eFT508 eFT508-0009 tomivosertib
Sponsor: Effector Therapeutics
Start date: 2018-11-27; Completion date: 2020-04-27
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Phase 2 Open-label Study examines the efficacy, safety, tolerability, and pharmacokinetics (PK) of tomivosertib (eFT508) in Patients with advanced CRPC.

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

Detailed description:
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.

Arms: arm 1: Tomivosertib (eFT508) is a novel small-molecule, investigational drug being developed by eFFECTOR Therapeutics, Inc. as an anticancer therapy. Tomivosertib (eFT508) down regulates AR and acts by inhibiting mitogen-activated protein kinase-interacting serine/threonine kinase-1 (MNK1) and MNK2.
Interventions: intervention 1: eFT508
Intervention descriptions: intervention 1: This Phase 2 study examines the efficacy, safety, tolerability, and 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.

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL: eFT508-0009 
 
Protocol Title: 
A Phase 2 Non-randomized Open-label Study Examining the 
Effect of eFT508 in Patients with Advanced Castrate-resistant 
Prostate Cancer (CRPC)  
Investigational Product: 
eFT508 (also referred to as tomivosertib) 
Protocol Number: 
eFT508-0009 
Study Sponsor: 
eFFECTOR Therapeutics, Inc. 
11180 Roselle Street, Suite A 
San Diego, CA 92121 
United States 
Protocol Version (Date): 
Version 3.0 (30 November 2018) 
Previous Versions (Dates): 
Version 2.0 (24 April 2018) 
Version 1.0 (19 April 2018) 
 
Confidentiality Statement 
This document contains information that is confidential and proprietary to eFFECTOR Therapeutics, Inc. 
(eFFECTOR) and is provided for the purpose of conducting a clinical trial for eFFECTOR. The contents of this 
document may be disclosed only to study personnel, the Institutional Review Board/Independent Ethics Committee, 
or duly authorized representatives of regulatory agencies for this purpose under the condition that they maintain 
confidentiality. The contents of this document may not be used in any other clinical trial, disclosed to any other 
person or entity, or published without prior written permission from eFFECTOR. 


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PROTOCOL SYNOPSIS 
Protocol Number 
eFT508-0009 
Study Drugs 
eFT508 (tomivosertib) 
Protocol Title 
A Phase 2 Non-randomized Open-label Study Examining the Effect of eFT508 in 
Patients with Advanced Castrate-resistant Prostate Cancer (CRPC) 
Phase 
Phase 2 
IND Number 
127168 
Study Sponsor 
eFFECTOR Therapeutics 
11180 Roselle Street, Suite A 
San Diego, CA 92121 
Study Centers Planned 
Up to 10 sites globally 
Background 
eFT508, referred to hereafter as tomivosertib, is a novel small-molecule, 
investigational drug being developed by eFFECTOR Therapeutics, Inc. as an 
anticancer therapy. Tomivosertib acts by inhibiting mitogen-activated protein kinase-
interacting serine/threonine kinase-1 (MNK1) and MNK2. MNK1/2 kinases are 
activated by mitogen-activated protein kinase (MAPK) signaling and integrate signals 
from several oncogenic and immune signaling pathways (including receptor tyrosine 
kinases, RAS, PI3K, T and B cell receptors) selectively regulating gene expression at 
the level of mRNA translation by phosphorylating eukaryotic initiation factor 4E 
(eIF4E) and other key effector proteins. Phosphorylation of these translational 
regulators by MNK1 and MNK2 selectively regulates the stability and translation of a 
subset of cellular mRNA that include factors that drive tumor growth and survival, 
effectors of anti-tumor immune response, cytokines, and chemokines. These 
collective actions result in significant in vivo tumor growth inhibition (TGI) and 
regression in multiple mouse and human tumor models, including xenograft, 
patient-derived explant (PDX), and genetically engineered models of breast cancer; 
hepatocellular carcinoma (HCC); non-small cell lung cancer; prostate cancer; and 
diffuse large B cell lymphoma.  
Tomivosertib has demonstrated significant in vivo activity in multiple preclinical 
models of prostate cancer. These models include the 22Rv1 xenograft and multiple 
PDX models. Tomivosertib treatment has been shown to lead to downregulation of 
androgen receptor (AR) expression in vitro and decreases circulating prostate-specific 
antigen (PSA) in vivo.   
Tomivosertib has completed dose escalation in Phase 1 studies in patients with 
advanced solid tumors and hematological malignancies. The drug is orally 
administered on a twice-daily (BID) schedule and the recommended Phase 2 dose of 
200 mg BID has been shown to inhibit the phospho-eIF4E (P-eIF4E) target in on-
treatment tumor biopsies. 
To date adverse events (AEs) have been mild to moderate with a focus on 
gastrointestinal (GI) symptoms (nausea, vomiting), fatigue, tremor, and 
hypercalcemia. 
The mainstay of treatment of recurrent, locally advanced and metastatic prostate 
cancer is long-term androgen deprivation therapy (ADT); however, most patients will 
have disease progression to CRPC. Data generated over the last 3 years suggest that 
adding either chemotherapy (docetaxel) or novel hormonal therapy such as 
abiraterone or enzalutamide to ADT can provide significant survival advantage over 
ADT alone in patients with locally advanced or hormone-sensitive metastatic disease. 
Very recent data generated in patients with CRPC M0 biochemical relapse have 


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Protocol: eFT508-0009 
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demonstrated that both apalutamide and enzalutamide deliver very significant 
improvements in metastasis- free survival (MFS) vs placebo. Once progression on 
apalutamide and/or abiraterone and/or enzalutamide therapies has occurred, 
chemotherapy and radium 223 are remaining options providing modest improvements 
in overall survival at the expense of significant morbidity. With the increasing 
realization that CRPC is a genetically heterogeneous disease, the search has begun for 
actionable molecular alterations. Regardless of the identification of such alterations, 
there is unequivocal evidence that the AR signaling axis remains active during all 
stages of prostate cancer. Thus, an agent like tomivosertib that has the potential to 
downregulate expression of AR irrespective of mutation or splice variant status could 
present an attractive option for patients. 
Study Design 
This Phase 2 study examines the efficacy, safety, tolerability, and pharmacokinetics 
(PK) of tomivosertib 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. A Simon 2-stage minimax design 
(Simon 1989) will target the desired tumor response rate of tomivosertib 
monotherapy. Time-to-event parameters will also be collected. Circulating tumor 
cells (CTCs) will be measured on all patients and efficacy parameters will be 
correlated with their presence/absence and with their particular characteristics (eg, 
presence of mutations and splice variants). Blood samples for PK analysis will be 
collected, and PK data will be assessed and correlated, as appropriate, with efficacy. 
Study Objectives 
Primary Objective 
• 
To assess anti-tumor response of tomivosertib in advanced CRPC 
Secondary Objectives 
• 
To further characterize anti-tumor activity in terms of time-to-event data 
• 
To characterize the safety, tolerability, and PK of tomivosertib 
Exploratory Objectives  
• 
To correlate efficacy with the characteristics of CTCs and P-eIF4E status of 
available tumor tissue (archival or fresh) 
Study Endpoints 
Primary Endpoint 
Anti-tumor response will be defined on the basis of the following co-primary 
endpoints. A patient will be considered a responder if he achieves either of the 
following outcomes: 
• 
A ≥50% PSA decline from baseline at any time point after therapy and 
maintained for ≥4 weeks 
• 
Objective response according to immune-related Response Evaluation 
Criteria in Solid Tumors (iRECIST)  
Secondary Endpoints 
• 
PSA progression-free survival (Prostate-Specific Antigen Working Group 2 
[PCWG2] criteria)  
• 
Clinical and radiological progression-free survival (iRECIST) 
• 
PCWG2 bone progression-free survival  
• 
Overall Survival (OS) 
• 
AEs as characterized by type frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI 
CTCAE] v 5), timing, seriousness, and relationship to drug(s) 
• 
Laboratory abnormalities as characterized by type, frequency, severity (as 
graded by NCI CTCAE v 5), and timing 


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• 
PK plasma concentration taken at the anticipated maximum and minimum 
plasma concentrations for tomivosertib 
Exploratory Endpoints 
• 
CTCs 
• 
P-eIF4E status of available tumor tissue (fresh or archival) 
Number of Patients 
Planned 
Approximately 30 patients will be enrolled to have 27 evaluable patients to target a 
tumor response rate of ≥20% 
Target Population 
The target population comprises adult CRPC male patients with adequate 
performance status and organ function who have histologically confirmed 
adenocarcinoma of the prostate with available tissue (archival or fresh) and who have 
PSA progression on treatment with apalutamide and/or abiraterone and/or 
enzalutamide and for whom no suitable curative therapy exists. 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for 
participation in this study: 
1. Men ≥18 years 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
3. Histologically or cytologically confirmed (by clinical site) adenocarcinoma of 
the prostate without neuroendocrine differentiation or small cell features. 
4. Ongoing androgen deprivation therapy with a GnRH analog or bilateral 
orchiectomy (surgical or medical castration) 
5. Serum testosterone ≤1.73 nmol/L (50 ng/dL) at screening 
6. 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 
7. 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 
8. Completion of all previous therapy for the treatment of cancer 4 weeks before 
the start of study therapy.  
9. 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]) 
10. 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) 
11. 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 


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• 
Serum bilirubin 1.5 x ULN (unless due to Gilbert’s syndrome or 
hemolysis ≤3 x ULN) 
12. Adequate renal function: 
• 
Serum creatinine 1.5 mg/dL and/or creatinine clearance ≥30 mL/min 
using Cockcroft Gault equation (Appendix 13.4) 
13. 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 
14. Estimated life expectancy >12 weeks before the start of study therapy 
15. 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. 
16. 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 
Patients who meet any of the following exclusion criteria are not to be enrolled in this 
study: 
1. 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  
2. 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. 
3. 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 
4. 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  
5. Symptomatic or impending cord compression unless appropriately treated 
beforehand and clinically stable 
6. Patients with gastrointestinal disorders likely to interfere with absorption of study 
medication 
7. Major surgery within 4 weeks before the start of study therapy 
8. Prior treatment with chemotherapy within 3 weeks or at least 4 half-lives, 
whichever is longer, before the start of study therapy  
9. Prior therapy with any known inhibitor of MNK-1 or MNK-2 
10. Treatment with 5-alpha reductase inhibitors within 4 weeks of enrollment 


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11. Prior flutamide treatment within 4 weeks before the start of study therapy and 
evidence of withdrawal response 
12. Bicalutamide or nilutamide within 6 weeks before the start of study therapy and 
evidence of withdrawal response 
13. Enzalutamide or abiraterone or apalutamide 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 
14. Use of herbal products that may have hormonal anti-prostate cancer activity 
and/or are known to decrease PSA levels (eg, saw palmetto). Exception: Patients 
using these products who have not had any anti-tumor effect including 
reduction in PSA levels attributed to their use and there is no potential for 
drug interaction with tomivosertib  
15. Current use of immunosuppressive medication at the time of randomization, 
EXCEPT for the following:  
a. 
Intranasal, inhaled, topical steroids, or local steroid injection (eg, 
intra-articular injection);  
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of 
prednisone or equivalent;  
c. 
Steroids as premedication for hypersensitivity reactions (eg, 
computed tomography [CT] scan premedication)  
16. 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) 
17. Concurrent participation in another therapeutic clinical trial 
18. 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 
Dosage Forms and 
Strengths 
Tomivosertib is provided as 100 mg capsules for oral administration of 200 mg BID. 
Sample Size 
Total sample size will include up to 27 evaluable patients.  
Simon’s 2-stage design will be used to evaluate the tumor response rate. The null 
hypothesis that the true response rate is 5% will be tested against a one-sided 
alternative. In the first stage, 13 patients will be accrued. If there are no responses in 
these 13 patients after a minimum of 16 weeks of exposure to tomivosertib, the study 
will be stopped. Otherwise, 14 additional evaluable patients will be accrued for a total 
of 27 patients. The null hypothesis will be rejected if 4 or more responses are 
observed in 27 patients.  
 


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SCHEDULE OF EVENTS  
 
Screening 
Therapy 
End of 
Treatment 
Post-Treatment 
Follow-up 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Day 
-28 to -1 
1 
8 
15 
1 
8 
15 
1 
 
≥30 days 
Long-
term 
Visit Window, days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
+14 
 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
Tomivosertib administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
Written informed consenta 
X 
 
 
 
 
 
 
 
 
 
 
Medical historyb 
X 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
 
 
X 
 
 
X 
X 
 
 
Height, weightc 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
12-lead ECGe 
X 
X 
 
 
X 
 
 
X 
X 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
Hematologyf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum chemistryg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PSAh  
X 
X 
 
 
X 
 
 
X 
X 
 
 
Circulating tumor cellsi  
X 
X 
 
 
X 
 
 
X 
X 
 
 
Coagulationj 
X 
 
 
 
 
 
 
 
X 
 
 
Urinalysisk 
X 
X 
 
 
 
 
 
Xk 
X 
 
 
Blood for genetic markerst 
Xt 
Xt 
 
 
 
 
 
 
 
 
 
Blood for pharmacokineticsl  
 
X 
 
Xm 
Xn 
 
 
Xo 
 
 
 
Optional Tumor tissue (archival or fresh) 
X 
 
 
 
 
 
 
 
 
 
 
Disease assessments 
 
 
 
 
 
 
 
 
 
 
 
Physical examination/assessmentp 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Radiology examination inc bone scanq 
X 
 
 
 
 
 
 
X 
X 
 
Xs 
Posttherapy safety assessmentr 
 
 
 
 
 
 
 
 
 
X 
 
Long-term follow-ups 
 
 
 
 
 
 
 
 
 
 
X 
 


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Protocol: eFT508-0009 
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a. 
Informed consent to be obtained before other study procedures are performed. 
b. 
Medical history to include recording of cancer history, previous anticancer therapies (including prior hormonal interventions), surgical history, past and ongoing 
medical conditions, and review of systems 
c. 
Height to be obtained at Screening only.  
d. 
Vital signs (blood pressure, pulse, temperature) will be collected with the patient in a supine position.  
e. 
12-lead ECGs will be obtained with patients in a supine position. ECGs will be collected at Screening, Day 1 of every cycle, and at the end of treatment. 
f. 
Hematology testing will include hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils; platelet count. On tomivosertib clinic dosing days, predose samples should be obtained and results assessed before tomivosertib administration. 
g. 
Serum chemistry studies will include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphorus, magnesium, total protein, albumin, 
ALT, AST, ALP, CK, LDH, total bilirubin, uric acid. On tomivosertib clinic dosing days, predose samples should be obtained and results assessed before tomivosertib 
administration. Serum testosterone to be confirmed at baseline as ≤1.73 nmol/L (50 ng/dL). 
h. 
PSA testing –At Screening, Day 1 of every cycle, and at the end of treatment. PSA response by PCWG2 criteria must be confirmed ≥4 weeks later. The blood sample is 
collected before the morning dose. 
i. 
Circulating Tumor Cells will be assessed at Screening or predose on Cycle 1 Day 1, Day 1 of every cycle, and at the end of treatment. 
j. 
Coagulation studies will include PT, aPPT, INR at Screening and end of treatment Visit.  
k. 
Urinalysis will include specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase as assessed by dipstick. A microscopic 
urinalysis evaluating white blood cells, red blood cells, epithelial cells, bacteria, cast and crystals, will be performed only as needed. On tomivosertib clinic dosing 
days, predose samples should be obtained and assessed before tomivosertib administration. To be performed at Screening, Cycle 1 Day 1, Cycle 3 Day 1, and every odd 
cycle. 
l. 
Blood samples will be collected before the tomivosertib morning dose and at 3 ±1 hours after the tomivosertib morning dose. The date and actual nominal time of 
blood sampling must be recorded. If a patient mistakenly takes tomivosertib at home on days when it should be administered at the site for PK sampling, blood samples 
for tomivosertib PK should not be collected on those days, and the patient should return at the next available time for tomivosertib administration at the clinical site 
with tomivosertib PK sampling.  
m. The predose sample should be obtained at 12 ± 1 hours postdose from the Cycle 1 Day 14 tomivosertib evening dose. The time of the tomivosertib Cycle 1 Day 14 
evening dose administered at home, prior to PK blood collection, should also be recorded. 
n. 
The predose sample should be obtained at 12 ± 1 hours postdose from the Cycle 1 Day 28 tomivosertib evening dose. The time of the tomivosertib Cycle 1 Day 28 
evening dose administered at home, prior to PK blood collection, should also be recorded. 
o. 
Cycles 4 and 8 only. The predose sample should be obtained at 12 ± 1 hours postdose from Cycle 3 Day 28 and Cycle 7 Day 28 tomivosertib evening doses (ie, predose 
on Cycle 4 Day 1 and Cycle 8 Day 1). The time of the tomivosertib Cycles 3 and 7 Day 28 evening doses administered at home, prior to PK blood collection, should 
also be recorded. 3 ±1 hour postdose samples will also be collected on Day 1 of Cycles 4 and 8. 
p. 
Physical examination is required at Screening and Cycle 1 Day 1. A physical assessment, which can be done by a research nurse, may be performed at other visits. 
q. 
Radiology examination will include CT (and may include PET, if relevant) or MRI imaging of chest, abdomen, and pelvis. The same method of assessment (CT, 
CT/PET, MRI) and the same technique should be used to characterize each identified and reported lesion at Screening and while on study. Evaluations are to be 
performed during Screening within 28 days prior to the initiation of study therapy; then every 8 ± 1 weeks for 1 year, then every 12 ± 1 weeks until confirmed 
progression. An end-of-treatment radiology assessment should be performed unless the patient already has radiographic confirmation of PD ≤4 weeks prior to 
permanent study drug discontinuation. 
Bone scans will be performed at Screening, every 8 ± 1week for 1 year, then every 12 ± 1week until confirmed progression. New bone lesions are to be confirmed with 
repeat scan ≥ 6 weeks later.  


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r. 
Posttherapy safety assessment will be performed after permanent cessation of tomivosertib to follow patients for any drug-related adverse events and/or ongoing serious 
adverse events. Patients will be followed for ≥30 days or until those events have resolved or become stable, whichever occurs later. Follow-up may be obtained in 
person or by telephone contact. 
s. 
Long-term follow-up information will be obtained in all surviving patients who permanently discontinue study therapy. For patients who discontinue study treatment 
without radiologic disease progression, every effort should be made to continue monitoring disease status by tumor imaging per standard of care until the start of a new 
anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first. Data on post-study therapies for the 
cancer, and on survival will be collected. Such information may be collected at ~3- to 6-month intervals at the Sponsor’s discretion through 18 months. This long-term 
follow-up information will be gathered during routine clinic visits, other study site contact with the patients, or via telephone or e-mail with the patients/caregivers or 
referring physician offices. These data will be collected in the source documents (eg, patient medical record) and transcribed to a specific eCRF. 
t. 
This assessment may be performed at Screening or Cycle 1 Day 1 prior to first dose of tomivosertib 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea 
nitrogen; CK, creatine kinase; CT, computed tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case report form; INR, 
international normalized ratio; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PCWG2, Prostate-Specific Antigen Working Group 2; PD, progressive disease; 
PET, positron emission tomography; PK, pharmacokinetics; PSA, prostate-specific antigen; PT, partial thromboplastin time 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................2 
SCHEDULE OF EVENTS ..............................................................................................................7 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF IN-TEXT TABLES ........................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................16 
1 
INTRODUCTION ................................................................................................................18 
 
Unmet Medical Need .......................................................................................................18 
 
Prostate Cancer ...........................................................................................................18 
 
Biological Significance of the p38 Mitogen-Activated Protein 
Kinase-Interacting Protein Kinases in Oncology ............................................................19 
 
Tomivosertib ....................................................................................................................20 
 
Rationale for Study Design and Dose Regimen Selection ..............................................21 
2 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................23 
 
Study Objectives ..............................................................................................................23 
 
Primary Objective .......................................................................................................23 
 
Secondary Objectives .................................................................................................23 
 
Exploratory Objectives ...............................................................................................23 
 
Study Endpoints ...............................................................................................................23 
 
Primary Endpoint ........................................................................................................23 
 
Secondary Endpoints ..................................................................................................23 
 
Exploratory Endpoints ................................................................................................24 
3 
STUDY DESIGN .................................................................................................................25 
 
Study Overview ...............................................................................................................25 
 
Duration of Study ............................................................................................................25 
4 
STUDY ENROLLMENT AND WITHDRAWAL ..............................................................26 
 
Study Population .............................................................................................................26 
 
Inclusion Criteria ........................................................................................................26 
 
Exclusion Criteria .......................................................................................................27 
 
Enrollment and Method of Assigning Patients to Treatment Groups .............................29 
 
Study Blinding .................................................................................................................29 
 
Patient Withdrawal and Replacement .............................................................................29 


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Discontinuation of Study Drug ...................................................................................29 
 
Completion of Study ...................................................................................................30 
 
Premature Termination of the Study ...........................................................................30 
5 
STUDY DRUG ....................................................................................................................31 
 
Tomivosertib (eFT508) ...................................................................................................31 
 
Description ..................................................................................................................31 
 
Manufacturing, Packaging, and Labeling ...................................................................31 
 
Site Storage .................................................................................................................31 
 
Home Storage .............................................................................................................31 
 
Dispensing ..................................................................................................................31 
 
Compliance and Accountability .................................................................................32 
 
Tomivosertib Disposal or Return ................................................................................32 
 
Tomivosertib Administration......................................................................................32 
 
Tomivosertib Dose Schedule Interruptions and Vomited Doses ................................33 
 
Tomivosertib Dose Modifications for Drug-Related Toxicity ...................................33 
6 
CONCOMITANT THERAPIES, SUPPORTIVE CARE, AND OTHER 
CONSIDERATIONS ...........................................................................................................35 
 
Concomitant Therapies ....................................................................................................35 
 
Acceptable Concomitant Medications and Procedures ..............................................35 
 
Prohibited Concomitant Medications and/or Treatments ...........................................35 
 
Rescue Medication and Supportive Care ........................................................................36 
 
General Supportive Care Guidelines ..........................................................................36 
 
Other Considerations .......................................................................................................37 
 
Contraception ..............................................................................................................37 
 
Diet .............................................................................................................................38 
7 
STUDY PROCEDURES AND ASSESSMENTS ...............................................................39 
 
Medical History, Demographics, and Prior and Concomitant Medications and 
Therapies .........................................................................................................................39 
 
Medical History ..........................................................................................................39 
 
Demographics .............................................................................................................39 
 
Genetic Markers ..........................................................................................................39 
 
Prior and Concomitant Medications and Therapies ........................................................39 
 
Safety Assessments .........................................................................................................40 


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Adverse Events ...........................................................................................................40 
 
Physical Examination/Assessment .............................................................................40 
 
Vital Signs ..................................................................................................................40 
 
12-Lead Electrocardiograms .......................................................................................40 
 
Local Laboratory Assessments ...................................................................................41 
 
Eastern Cooperative Oncology Group Performance Status ........................................41 
 
Efficacy Assessments ......................................................................................................42 
 
Prostate-specific Antigen ............................................................................................42 
 
Radiology Examination ..............................................................................................42 
 
Bone Scan ...................................................................................................................43 
 
Determining Disease Progression ...............................................................................43 
 
Pharmacokinetics Analysis ..............................................................................................43 
 
Exploratory Assessments .................................................................................................44 
 
Circulating Tumor Cells .............................................................................................44 
 
P-eIF4E .......................................................................................................................44 
8 
SCHEDULE OF EVENTS ...................................................................................................45 
 
Screening Period ..............................................................................................................46 
 
Treatment Period (4-Week [28-day]) Treatment Cycles) ...............................................47 
 
Cycle 1 ........................................................................................................................47 
 
Cycle 2 ........................................................................................................................50 
 
Cycle 3 Day 1 (3 Days) ..........................................................................................52 
 
Radiologic Examinations ............................................................................................54 
 
End-of-Treatment Visit (+14 Days)............................................................................54 
 
Post-Treatment Follow-Up Period ..................................................................................55 
 
30-Day Follow-Up ......................................................................................................55 
 
Long-Term Follow-Up ....................................................................................................55 
9 
ADVERSE EVENT MONITORING ...................................................................................56 
 
Adverse Events ................................................................................................................56 
 
Adverse (Drug) Reaction ............................................................................................57 
 
Unexpected Adverse Drug Reaction ..........................................................................57 
 
Assessment of Adverse Events by the Investigator ....................................................57 
 
Serious Adverse Events ...................................................................................................58 


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Serious Adverse Event Reporting − Procedures for Investigators ..................................59 
 
Special Situation Reporting Requirements ......................................................................59 
 
Definitions of Special Situations ................................................................................59 
 
Partner Pregnancy .......................................................................................................60 
 
Instructions for Reporting Special Situations .............................................................60 
 
Expedited Reporting ........................................................................................................61 
10 
STATISTICAL CONSIDERATIONS .................................................................................62 
 
General Considerations ...................................................................................................62 
 
Analysis Populations .......................................................................................................62 
 
Determination of Sample Size .........................................................................................62 
 
Analysis Methods ............................................................................................................63 
 
Disposition, Demographics, and Disease History ......................................................63 
 
Study Drug Exposure and Compliance .......................................................................63 
 
Prior and Concomitant Medications ...........................................................................63 
 
Safety Analyses ..........................................................................................................64 
 
Efficacy Analyses .......................................................................................................64 
 
Pharmacokinetic Analyses ..........................................................................................65 
 
Exploratory Analyses ..................................................................................................65 
 
Interim Analysis ..............................................................................................................66 
11 
STUDY ADMINISTRATION AND RESPONSIBILITIES ...............................................67 
 
General Investigator Responsibilities ..............................................................................67 
 
Protocol Compliance .......................................................................................................67 
 
Protocol Deviations ....................................................................................................67 
 
Compliance with Ethical and Regulatory Guidelines .....................................................68 
 
Institutional Review Board ..............................................................................................68 
 
Informed Consent Process ...............................................................................................69 
 
Confidentiality .................................................................................................................70 
 
Study Files and Retention of Records and Biological Samples ......................................71 
 
Patient Screening Log ......................................................................................................72 
 
Modifications of the Protocol or Informed Consent Documents ....................................72 
 
Case Report Forms ..........................................................................................................72 
 
Clinical Monitoring .........................................................................................................73 
 
Inspections .......................................................................................................................73 


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Data Management ............................................................................................................73 
 
Clinical Study Insurance ..................................................................................................74 
 
Communications with Regulatory Authorities ................................................................74 
 
Publication and Information Disclosure Policy ...............................................................74 
 
Study Discontinuation .....................................................................................................74 
12 
REFERENCES .....................................................................................................................75 
13 
APPENDICES ......................................................................................................................78 
 
Sponsor Protocol Approval .............................................................................................79 
 
Principal Investigator Agreement ....................................................................................80 
 
Eastern Cooperative Oncology Group Performance Status Scale ...................................81 
 
Cockcroft-Gault Method for Estimating Creatinine Clearance .......................................82 
 
Strong Inhibitors and Inducers of Cytochrome P450 (CYP)3A4 ....................................83 
 
Immune-Related Response Evaluation Criteria in Solid Tumors ...................................84 
 
Definitions of Disease .................................................................................................84 
 
Definitions of Target and Nontarget Lesions .............................................................85 
 
Guidelines for Evaluation of Disease .........................................................................85 
 
iRECIST .....................................................................................................................87 
 
 


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LIST OF IN-TEXT TABLES 
Table 1: 
Dose-Modification Guidelines for Tomivosertib-Related 
Treatment-Emergent Adverse Events ........................................................................34 
Table 2: 
Protocol-Recommended Contraception Methods for Study Participants and 
Female Partners ..........................................................................................................38 
Table 3: 
Diagnostic and Safety Laboratory Tests and Parameters ...........................................41 
Table 4: 
iRECIST New Progression Confirmation Rules ........................................................88 
Table 5: 
Comparison Between RECIST 1.1 and iRECIST ......................................................89 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADT 
androgen deprivation therapy 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
AV 
atrioventricular 
BID 
twice daily 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CPD 
clinical progression of disease 
CR 
complete response 
CRPC 
castration-resistant prostate cancer 
CT 
computed tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
Dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ERK 
extracellular kinase 
EDC 
electronic data capture 
eIF4E 
eukaryotic initiation factor 4E 
FDA 
Food and Drug Administration 
G-CSF 
granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GnRH 
gonadotropin-releasing hormone 
HCC 
hepatocellular carcinoma 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
iRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
IV 
intravenous(ly)  
MAPK 
mitogen-activated protein kinase 
MFS 
metastasis-free survival 
MNK 
mitogen-activated protein kinase-interacting serine/threonine kinase 
MRI 
magnetic resonance imaging 


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Abbreviation 
Definition 
mRNA 
messenger ribonucleic acid 
NCI 
National Cancer Institute 
NE 
nonevaluable 
OS 
overall survival 
PCWG2 
Prostate-Specific Antigen Working Group 2 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PDX 
patient-derived explant 
P-eIF4E 
phospho-eIF4E 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
orally 
PR 
partial response 
PSA 
prostate-specific antigen 
PTEN 
phosphatase and tensin homolog 
QD 
once daily 
RANKL 
receptor activator of nuclear factor kappa-B ligand 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
TEAE 
treatment-emergent adverse event 
TGI 
tumor growth inhibition 
ULN 
upper limit of normal 
UPD 
unconfirmed progressive disease 
UTR 
untranslated region 
Note: Abbreviations that are only used in tables are defined in the table footnotes.  


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1 INTRODUCTION 
 Unmet Medical Need 
The mainstay of treatment of recurrent, locally advanced and metastatic prostate cancer is long-
term androgen deprivation therapy (ADT); however, most patients will have disease progression 
to castrate-resistant prostate cancer (CRPC). Data generated over the last 3 years suggest that 
adding either chemotherapy (docetaxel) or novel hormonal therapy such as abiraterone or 
enzalutamide to ADT can provide significant survival advantage over ADT alone in patients 
with locally advanced or hormone-sensitive metastatic disease. Very recent data generated in 
patients with CRPC M0 biochemical relapse have demonstrated that both apalutamide and 
enzalutamide deliver very significant improvements in metastasis-free survival (MFS) vs 
placebo. Once progression on apalutamide and/or abiraterone and/or enzalutamide therapies has 
occurred, chemotherapy and radium 223 are remaining options providing modest improvements 
in overall survival at the expense of significant morbidity. With the increasing realization that 
CRPC is a genetically heterogeneous disease, however, the search has begun for actionable 
molecular alterations. Regardless of the identification of such alterations, there is unequivocal 
evidence that the androgen receptor (AR) signaling axis remains active during all stages of 
prostate cancer. Thus, an agent like eFT508 (referred to here after as tomivosertib) that has the 
potential to downregulate expression of AR irrespective of mutation or splice variant status could 
present an attractive option for patients. 
 Prostate Cancer 
Prostate cancer is one of the most common causes of cancer related deaths in the world 
(Zhou 2016). Since the first documentation of regression of metastatic disease by surgical 
castration followed by the introduction of chemical ADT, ADT has become a cornerstone of 
recurrent/metastatic disease management (Prostate Cancer Trialists’ Collaborative Group 2000). 
Androgens control normal and malignant prostate tissue growth by activation of signaling 
through the AR, thus removal of a source of androgen by surgical or chemical castration will 
deprive malignant cells of a major stimulus for growth. Despite this major advance most patients 
will develop resistance to ADT and median survival of patients with metastatic disease is only on 
the order of 3 years (Wu 2014). 
Attempts to improve the outcomes for patients with metastatic CRPC have involved the use of 
chemotherapy with agents such as docetaxel (Vale 2016) and secondary hormones such as 
abiraterone (Ryan 2013) and enzalutamide (Beer 2014). Recently the results of 3 randomized 
studies ˗ CHAARTED (Sweeney 2016), STAMPEDE (James 2016), and GETUG-15 
(Gravis 2013) ˗ have demonstrated the benefit of adding docetaxel to ADT and this regimen has 
become a standard of care for patients with metastatic castration-sensitive prostate cancer. 
Additionally, the combination of ADT and abiraterone in this same metastatic castration-
sensitive population has shown benefit over ADT alone in both the STAMPEDE study and the 
LATITUDE study (Fizazi 2017). 
Further developments in the treatment of metastatic prostate cancer are well summarized in a 
recent review (Sartor 2018). What has been clearly established is that disease progression after 
ADT and secondary hormones continues to rely on signaling through the AR, which may be 
gene amplified, overexpressed, or mutated leading to constitutive activation (Jernberg 2017) 


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despite systemic castrate levels of androgen. Numerous approaches to disrupt AR signaling are 
now being tested in the clinic. 
 Biological Significance of the p38 Mitogen-Activated Protein 
Kinase-Interacting Protein Kinases in Oncology 
Dysregulated translation of messenger ribonucleic acid (mRNA) plays a significant role in the 
pathogenesis of multiple solid tumors and hematological malignancies. Mitogen-activated 
protein kinase (MAPK)-interacting serine/threonine kinase (MNK)1 and MNK2 are key 
regulators of mRNA translation, integrating signals from oncogenic and immune signaling 
pathways (including RAS, PI3K, p38, TLR, T and B cell receptors) through phosphorylation of 
eukaryotic initiation factor (eIF)4E and other key effector proteins. Phosphorylation of these 
mRNA binding proteins selectively regulates expression of a subset of mRNA that control 
tumor/stromal cell signaling and shape the tumor microenvironment. MNK1 and MNK2 are 
activated in response to extracellular stimuli by the extracellular regulated kinases (ERK1/2) and 
p38 MAPK pathways that are known to play important roles in mediating oncogenesis, 
apoptosis, and inflammation (Joshi 2014). MNK1/2 are activated in response to treatment with 
growth factors, mitogens, and stress-inducing agents, as well as by cytokines (Waskiewicz 1997, 
Wang 1998, Ueda 2004, Parra 2005, Joshi 2009, Joshi 2011). 
MNK1 and MNK2 phosphorylate several downstream effectors, in particular eIF4E 
(Wang 1998). eIF4E specifically binds the 5’ m7GpppN cap structure found in all eukaryotic 
mRNAs and plays a critical role in cap-dependent translation initiation as a central component of 
the eIF4F complex. eIF4E selectively regulates translation of mRNA containing specific 
sequences and/or structural elements in their 5’-untranslated regions (UTRs), including mRNAs 
involved in oncogenic transformation, tumor growth stimulation, and inhibition of apoptotic 
pathways (Strudwick 2002, Ruggero 2004, Topisirovic 2004, Culjkovic 2005, Phillips 2008, 
Truitt 2015). In addition, eIF4E and phosho-eIF4E (P-eIF4E) are upregulated in a variety of 
human cancers and are linked to poor prognosis and resistance to therapy (De Benedetti 1999, 
Furic 2010, Astanehe 2012, Adesso 2013). In prostate cancer, overexpression of eIF4E and 
increased P-eIF4E levels correlate with disease progression and resistance to hormonal therapies 
(Furic 2010). Studies in mouse models have shown that expression of activated MNK1 leads to 
increased eIF4E phosphorylation at serine 209 and promotes tumorigenesis (Wendel 2007). 
Conversely, knock-in mice carrying a mutant form of eIF4E that cannot be phosphorylated at 
S209A (mimicking MNK inhibition) are resistant to tumorigenesis in a phosphatase and tensin 
homolog (PTEN)-driven prostate cancer model (Furic 2010). Importantly, mutant cells or mutant 
animals lacking MNK1, MNK2, or carrying eIF4E (S209A) do not exhibit defects in cap-
dependent mRNA translation or general protein synthesis and do not show developmental, 
viability, or reproductive defects (Ueda 2004, Furic 2010). 
MNK1 and MNK2 also play a role in establishing a tumor-permissive microenvironment as 
important mediators of pro-inflammatory cytokine production (Joshi 2014). Pro-inflammatory 
cytokines and chemokines are key effectors within the tumor microenvironment that impact both 
tumor cell survival signaling and recruitment and/or suppression of infiltrating immune cells. 
MNK activation appears to promote the translation of inflammatory cytokines through 
stabilization of mRNA through mechanisms that involve AU-rich elements in the 3’-UTRs of the 
mRNAs for these proteins (Buxadé 2005, Buxadé 2008). Therefore, MNK inhibition would 


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re-shape the tumor microenvironment by downregulating pro-inflammatory cytokines and 
chemokines. 
Studies in MNK1- and MNK2-deficient mice show normal development of T cells, regulatory 
T cells, or natural killer cells and demonstrate normal cluster of differentiation (CD)8 cytotoxic 
T cell responses to bacterial or viral infection (Gorentla 2013). However, in the context of tumor 
infiltrating immune cells, MNK kinases play a key role in up-regulating production of the 
immune checkpoint receptor/ligands, programmed cell death protein 1 (PD-1), programmed cell 
death-ligand 1 (PD-L1), TIM3, and LAG3, which are key mediators of T cell exhaustion and 
immune suppression. In addition, the MNK kinases through regulation of IL-10 can influence 
regulatory T cell function, and activation of antigen-presenting cells. Thus, inhibition of MNK1 
and MNK2 has the potential to impact tumor antigen presentation and T cell response, tipping 
the balance towards a more effective anti-tumor immune response. Consistent with these 
findings, preclinical studies have further demonstrated that selective inhibition of MNK1 and 
MNK2 enhances anti-tumor immune response and potentiates the activity of anti-PD-(L)1 
antibodies.  
Collectively, these results suggest that the MNK-dependent phosphorylation of eIF4E is 
important for the translation of specific mRNAs involved in tumorigenesis, and that targeted 
inhibition of MNK1 and MNK2 may selectively achieve anti-tumor effects with acceptable 
safety. 
 Tomivosertib 
Tomivosertib is a novel small-molecule, investigational drug being developed by eFFECTOR 
Therapeutics, Inc. as an anticancer therapy. Tomivosertib acts by selectively inhibiting MNK1 
and MNK2. MNK1/2 kinases are activated by MAPK signaling and integrate signals from 
several oncogenic and immune signaling pathways (including receptor tyrosine kinases, RAS, 
PI3K, T and B cell receptors) selectively regulating gene expression at the level of mRNA 
translation by phosphorylating eIF4E and other key effector proteins. Phosphorylation of these 
translational regulators by MNK1 and MNK2 selectively regulates the stability and translation of 
a subset of cellular mRNA that include factors that drive tumor growth and survival, effectors of 
anti-tumor immune response, cytokines, and chemokines. These collective actions result in 
significant in vivo tumor growth inhibition (TGI) and regression in multiple mouse and human 
tumor models, including xenograft, patient-derived explant (PDX), and genetically engineered 
models of prostate cancer; breast cancer; hepatocellular carcinoma (HCC); non-small cell lung 
cancer; and diffuse large B cell lymphoma. 
Tomivosertib has demonstrated significant in vivo activity in multiple preclinical models of 
prostate cancer. These models include the 22Rv1 xenograft and multiple PDX models. 
Tomivosertib treatment has been shown to lead to downregulation of AR expression in vitro and 
decreases circulating prostate-specific antigen (PSA) in vivo.  
Tomivosertibhas completed dose escalation in Phase 1 studies in patients with advanced solid 
tumors and hematological malignancies. The drug is orally administered on a twice-daily (BID) 
schedule and the recommended Phase 2 dose of 200 mg BID has been shown to provide >85% 
steady state target inhibition in peripheral blood cells and effectively inhibit phosphorylation of 
eIF4E in on-treatment tumor biopsies. This dose has now been confirmed as the recommended 
Phase 2 dose (RP2D) in both solid and hematological tumors 


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To date, adverse events (AEs) have been mild to moderate with a focus on gastrointestinal (GI) 
symptoms (nausea, vomiting), fatigue, tremor, and hypercalcemia. 
Detailed summaries of preclinical pharmacology, pharmacokinetic (PK), toxicology, and clinical 
studies of tomivosertib are provided in the tomivosertib Investigator’s Brochure (IB). 
 Rationale for Study Design and Dose Regimen Selection 
Patients with CRPC are usually offered novel hormonal therapy with either abiraterone or 
enzalutamide. After progression on these therapies has occurred, chemotherapy and radium 223 
are remaining options providing modest improvements in overall survival at the expense of 
significant morbidity. With the increasing realization that CRPC is a genetically heterogeneous 
disease, the search has begun for actionable molecular alterations. Regardless of the 
identification of such alterations, there is unequivocal evidence that the AR signaling axis 
remains active during all stages of prostate cancer. Thus, investigation of an agent like 
tomivosertib that has the potential to downregulate expression of AR irrespective of mutation or 
splice variant status could present an attractive option for patients.  
This Phase 2, open-label study will evaluate the efficacy, safety, and PK of tomivosertib 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. 
Patients will receive tomivosertib at a dose of 200 mg BID. The safety, PK, and 
pharmacodynamics of tomivosertib dosed on a once daily (QD) and BID schedule have been 
assessed in a Phase 1 multiple ascending dose escalation study. This study demonstrated that 
administration of 200 mg BID is well tolerated and maintains >85% steady state target inhibition 
over a 24-hour period in peripheral blood cells and completely inhibits the target in on-treatment 
biopsies 6 hours postdose.  
To date, 35 solid tumor patients have been exposed to the oral suspension of tomivosertib at 
doses ranging from 50 to 600 mg QD, 6 solid tumor patients have been exposed to the capsule 
formulation of tomivosertib at either 400 or 500 mg QD, 21 solid tumor patients have been 
exposed to the capsule formulation of tomivosertib at doses ranging from 100 to 400 mg BID, 
13 patients with hematological malignancies have been exposed to the capsule formulation of 
tomivosertib at either 200 or 300 mg BID, and 6 patients with hematological malignancies have 
been exposed to the oral suspension of tomivosertib at doses of 300 or 450 mg QD.  
Tomivosertib has been generally well tolerated to date. In the initial Phase 1 study in patients 
with solid tumors, a dose of 450 mg QD oral suspension was well tolerated in 8 patients without 
any dose-limiting toxicities (DLTs), whereas a dose of 600 mg QD exceeded conventional limits 
of tolerability. At 600 mg QD, 1 of 12 patients dosed experienced Grade 3 tremors, and 1 of 
12 patients dosed experienced Grade 3 nausea and vomiting. Additionally, Grade 3 increases in 
levels of circulating transaminases at the 600-mg QD dose level were observed in 1 patient, 
while bilirubin levels remained normal. Each of these AEs was reversible and resolved when 
tomivosertib dosing was suspended. In the Phase 1 dose escalation study in patients with 
lymphoma, 6 patients were dosed with the suspension formation, with 450 mg being the highest 
dose tested. Overall, the tolerability profile of the suspension formulation in lymphoma patients 
was similar to that observed in solid tumor patients, with an additional AE of hypercalcemia in 
1 patient dosed at 450 mg. 


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Both QD and BID dosing regimens of a more convenient capsule formulation have been tested, 
and a BID dosing regimen was selected to maximize target inhibition over time. The safety 
profile of the capsule is similar to that observed with the suspension formulation. In both 
hematological and solid tumor patients treated with the capsule formulation at doses ranging 
from 100 to 400 mg BID, the most common treatment-emergent adverse events (TEAEs) were 
low-grade GI events (eg, nausea, vomiting, and constipation), which were well managed with 
standard medications. Low-grade fatigue and tremor were also observed. Patient management, 
which involved holding the dose of drug until resolution of symptoms and then re-challenging at 
the same or lower dose, was generally successful. Hypercalcemia requiring treatment with 
bisphosphonates was observed in 2 patients with hematological malignancies. There was rapid 
resolution of the event in both cases and patients were able to continue treatment at a reduced 
dose. Finally, elevations in transaminases were documented, mainly in patients with metastatic 
solid tumors. However, the relationship of elevated transaminases to tomivosertib remains 
unclear because many of these patients had liver metastases, and the biochemical changes could 
have been a result of progressive disease (PD). 
The RP2D of tomivosertib administered by capsule has now been confirmed as 200 mg BID. 
Two of 6 solid tumor patients treated at 300 mg BID experienced DLTs: one with reversible 
grade 2/3 tremors and one with reversible grade 3 delirium. The dose of 400 mg BID was also 
not tolerated. In a cohort of 6 patients, 2 were unable to complete the required amount of dosing 
in Cycle 1 due to a spectrum of low grade AEs. 
Elevations in liver enzymes have also been noted in preclinical toxicology studies in dogs. 
Elevations were observed during the treatment period and were associated with minimal to mild 
bile duct hyperplasia but there was no evidence of liver cellular damage. Liver enzymes returned 
to normal during the 28-day off-treatment observation period. Thus, elevations in liver enzymes 
did not correlate with the lack of impaired liver function or the induction of microscopic liver 
damage. 
Tomivosertib was orally bioavailable with rapid absorption and a mean plasma half-life of 
approximately12 hours. Exposure increased with increased dose, although less than dose 
proportionally. BID dosing increased trough drug levels at least 2-fold compared to the same 
total daily dose given QD, leading to a selection of BID dosing for further development. 
The extent of target inhibition in tumor biopsies and in peripheral blood cells, which includes 
T cell populations, has been measured by determining the level of P-eIF4E after tomivosertib 
treatment. This assay has been used in preclinical tumor models to correlate the 
pharmacodynamic effect of tomivosertib on eIF4E phosphorylation with tumor growth 
inhibition. In dose escalation studies, clear evidence of substantial target inhibition that increases 
with dose and exposure to tomivosertib has been observed. Doses of tomivosertib at 100, 200, or 
300 mg BID maintained a >80% steady state inhibition of P-eIF4E in peripheral blood cells 
throughout a 24-hour period. This degree of target inhibition is well in excess of levels required 
to deliver maximal preclinical activity in multiple in vivo tumor models. Importantly, this 
analysis also demonstrated significant target inhibition in circulating T cells, one of the target 
populations for antitumor immune effect. The P-eIF4E biomarker has also been assessed in pre- 
and on-treatment tumor biopsies by immunohistochemistry. Analysis of 2 patients administered 
200 mg BID for 22 days demonstrated complete target inhibition 6 hours postdose. These data 
confirm the pharmacodynamic efficacy of the 200-mg BID dosing regimen in patient tumors and 
further validate the pharmacodynamic effects in peripheral blood cells. 


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2 STUDY OBJECTIVES AND ENDPOINTS 
 Study Objectives 
 Primary Objective 
• To assess anti-tumor response of tomivosertib in advanced CRPC 
 Secondary Objectives 
• To further characterize anti-tumor activity in terms of time-to-event data 
• To characterize the safety, tolerability, and PK of tomivosertib 
 Exploratory Objectives 
• To correlate efficacy with the characteristics of circulating tumor cells (CTCs) and 
P-eIF4E status of available tumor tissue (archival or fresh) 
 Study Endpoints 
 Primary Endpoint 
Anti-tumor response will be defined on the basis of the following co-primary endpoints. A 
patient will be considered a responder if he achieves either of the following outcomes: 
• A ≥50% PSA decline from baseline at any time point after therapy and maintained for 
≥4 weeks 
• Objective response according to immune-related Response Evaluation Criteria in Solid 
Tumors (iRECIST) 
 Secondary Endpoints 
• PSA progression-free survival (Prostate-Specific Antigen Working Group 2 [PCWG2] 
criteria)  
• Clinical and radiological progression-free survival (iRECIST) 
• PCWG2 bone progression-free survival 
• Overall Survival (OS) 
• AEs as characterized by type frequency, severity (as graded by National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] v 5), timing, 
seriousness, and relationship to drug(s) 
• Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI 
CTCAE v 5), and timing 
• PK plasma concentration taken at the anticipated maximum and minimum plasma 
concentrations for tomivosertib 


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 Exploratory Endpoints 
• CTCs 
• P-eIF4E status of available tumor tissue (fresh or archival) 
 


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3 STUDY DESIGN 
 Study Overview 
This Phase 2 study examines the efficacy, safety, tolerability, and PK of tomivosertib in 
advanced CRPC patients who have documented PSA progression on treatment with apalutamide 
and/or abiraterone and/or enzalutamide for whom no suitable curative therapy exists. A Simon 2-
stage minimax design (Simon 1989) will target the desired tumor response rate of tomivosertib 
monotherapy. Time-to-event parameters will also be collected. CTCs will be measured on all 
patients and efficacy parameters will be correlated with their presence/absence and with their 
particular characteristics (eg, presence of mutations and splice variants).  
Study drug will be administered in 4-week (28 day) treatment cycles. Patients will self-
administer tomivosertib orally (PO) at 200 mg BID. Study drug will be administered until 
disease progression (unless the patient is deriving clinical benefit, based on iRECIST 
[Seymour 2017 and http://recist.eortc.org/irecist/] and is clinically stable), unacceptable toxicity, 
the patient withdraws consent, the Investigator or Sponsor discontinues the patient, or the study 
is terminated. At the discretion of the Investigator, and with the Sponsor’s approval, patients who 
meet PSA progression criteria per PCWG2 may continue treatment with tomivosertib if the 
patient is perceived to be deriving clinical benefit. Patients who discontinue study drug 
permanently will remain on study for the acquisition of safety information for up to 30 days after 
the last dose of study drug, unless they withdraw consent for further follow-up, and for further 
collection of information regarding additional therapies for their cancer and survival. 
Safety assessments will include AE recording, physical examinations, vital sign measurements, 
electrocardiograms (ECGs), Eastern Cooperative Oncology Group (ECOG) performance status, 
and clinical safety laboratory tests. AEs and laboratory abnormalities will be graded using the 
adult NCI CTCAE v 5. 
Efficacy assessments will include PSA evaluations on Day 1 of each cycle and radiographic 
examinations (including bone scan) every 8 ± 1 weeks for 1 year, then every 12 ± 1 weeks until 
confirmed progression . Response will be evaluated using iRECIST. 
Blood samples for PK analysis will be collected, and PK data will be assessed and correlated, as 
appropriate, with efficacy findings. 
 Duration of Study 
The overall duration of the study is anticipated to be approximately 2 years from the first 
patient’s first visit until the last patient’s last visit. 
For regulatory reporting purposes, the end of the study is defined as the date the last patient 
completes the End-of-Treatment Visit or the last patient completes 6 months of therapy, 
whichever occurs first. 


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4 STUDY ENROLLMENT AND WITHDRAWAL 
Patients will be enrolled at approximately 10 study sites in the United States. Any questions 
regarding a patient’s eligibility should be discussed with the Sponsor before enrollment. 
 Study Population  
The target population comprises adult CRPC male patients with adequate performance status and 
organ function who have histologically confirmed adenocarcinoma of the prostate with available 
tissue (archival or fresh) and who have PSA progression on treatment with apalutamide and/or 
abiraterone and/or enzalutamide and for whom no suitable curative therapy exists. 
 Inclusion Criteria 
Study patients must meet all of the following inclusion criteria to be eligible for participation in 
this study: 
1. Men ≥18 years 
2. ECOG performance status of 0, 1, or 2 
3. Histologically or cytologically confirmed (by clinical site) adenocarcinoma of the prostate 
without neuroendocrine differentiation or small cell features.  
4. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) 
analog or bilateral orchiectomy (surgical or medical castration) 
5. Serum testosterone ≤1.73 nmol/L (50 ng/dL) at screening 
6. 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. 
7. 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 
8. Completion of all previous therapy for the treatment of cancer ≥4 weeks before the start of 
study therapy 
9. 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]) 
10. Adequate bone marrow function: 
• Absolute neutrophil count (ANC) ≥1.0 x 109/L 
• Platelet count ≥75 x 109/L 


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• Hemoglobin ≥80 g/L (8.0 g/dL or 4.9 mmol/L) 
11. 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) 
12. Adequate renal function: 
• Serum creatinine ≤1.5 mg/dL and/or creatinine clearance ≥30 mL/min using 
Cockcroft Gault equation (Appendix 13.4) 
13. 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 
14. Estimated life expectancy >12 weeks before the of study therapy 
15. 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. 
16. 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  
Patients who meet any of the following criteria are not to be enrolled in this study: 
1. 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. 
2. 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. 
3. 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 


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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 
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 QTcF >470 msec  
5. Symptomatic or impending cord compression unless appropriately treated beforehand and 
clinically stable 
6. Patients with gastrointestinal disorders likely to interfere with absorption of study medication 
7. Major surgery within 4 weeks before the start of study therapy 
8. Prior treatment with chemotherapy within 3 weeks or at least 4 half-lives, whichever is 
longer, before the start of study therapy 
9. Prior therapy with any known inhibitor of MNK-1 or MNK-2 
10. Treatment with 5-alpha reductase inhibitors within 4 weeks of enrollment 
11. Prior flutamide treatment within 4 weeks before the start of study therapy and evidence of 
withdrawal response 
12. Bicalutamide or nilutamide within 6 weeks before the start of study therapy and evidence of 
withdrawal response 
13. Enzalutamide or abiraterone or apalutamide within 4 weeks before the start of study therapy 
a.  Steroids given in conjunction with abiraterone musts be washed out for at least 2 weeks 
prior to Cycle 1 Day 1 unless investigator chooses to keep patient on a dose of 
≤10 mg/day prednisone or equivalent 
14. Use of herbal products that may have hormonal anti-prostate cancer activity and/or are 
known to decrease PSA levels (eg, saw palmetto) Exception: Patients using these products 
who have not had any anti-tumor effect including reduction in PSA levels attributed to 
their use and there is no potential for drug interaction with tomivosertib 
15. Current use of immunosuppressive medication at the time of randomization, EXCEPT for the 
following:  
a. Intranasal, inhaled, topical steroids, or local steroid injection (eg, intra-articular 
injection);  
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent); 
c. Steroids as premedication for hypersensitivity reactions (eg, computed tomography (CT) 
scan premedication) 
16. Use of a potent inhibitor or inducer of cytochrome CYP3A4 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) 
17. Concurrent participation in another therapeutic clinical trial 


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18. 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 
 Enrollment and Method of Assigning Patients to Treatment Groups 
All patients who sign the Informed Consent Document(s) to begin screening will be assigned a 
unique patient identifier comprising the study site number of enrollment and a sequentially 
ordered patient number. 
 Study Blinding 
This is a non-randomized, open-label study; therefore, the Sponsor, Investigator, and patient will 
know the study drug being administered. 
 Patient Withdrawal and Replacement 
 Discontinuation of Study Drug  
Unless otherwise indicated, a patient must permanently discontinue tomivosertib for any of the 
following reasons: 
• Patient requests to discontinue study drug 
• Clinical progression of disease according to iRECIST (iCPD)  
• Intolerable tomivosertib-related toxicity despite appropriate supportive care and dose 
modification 
• Development of an intercurrent illness or other substantial change in the patient’s 
condition or circumstances that prevents further administration of study drug or would 
place the patient at unacceptable risk, as determined by the Investigator in consultation 
with the Sponsor and its representatives 
• Development of an intercurrent illness or other substantial change in the patient’s 
condition or circumstances that requires use of a prohibited concomitant medication. 
• Initiation of treatment for the patient’s cancer with an off-study therapeutic regimen 
• Substantial noncompliance with study requirements that may increase the safety risk or 
may substantially compromise the interpretation of study results 
• Investigator decision 
• Patient becomes lost to follow-up 
• Discontinuation of the study by the Sponsor, relevant regulatory agencies, or Institutional 
Review Board (IRB). 
The date and the primary reason for discontinuing tomivosertib will be recorded on the electronic 
Case Report Form (eCRF). Every attempt should be made to complete the End-of-Treatment 
Visit assessments (see Section 8.2.5). Unless the patient withdraws consent for all study 
procedures, the patient will remain on study for acquisition of safety information through 


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30 days after the last dose of tomivosertib and for further collection of information regarding 
additional therapies for the cancer and survival. 
 Completion of Study 
This study includes a Post-Treatment Follow-up Period. Patients are considered to have 
completed the study when their date of death has been obtained or they complete 18-month 
post-treatment follow-up, whichever occurs first. If the study is closed prior to the patient’s 
death, the patient’s completion date will be the date of study closure. Patients that are no longer 
able to be reached for follow-up may have their survival status or date of death obtained through 
public records. 
 Premature Termination of the Study 
If the study is terminated prematurely or suspended for any reason (eg, patient death, new 
information leading to potentially unfavorable risk/benefit ratio, Sponsor’s decision, 
suspension/termination on regulatory authority request), the Investigator/institution should 
promptly inform the patients, assure appropriate management and follow-up for the patients, and, 
where required by the applicable regulatory requirement(s), inform the regulatory authority. 
 


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5 STUDY DRUG 
Study drug (tomivosertib) must not be used outside the context of this protocol. Under no 
circumstances should the Investigator or other site personnel supply study drug to other 
Investigators, patients, or clinics, or allow supplies to be used other than directed by this protocol 
without prior authorization from the Sponsor. 
 Tomivosertib (eFT508) 
 Description 
Tomivosertib is a small molecule that inhibits MNK1 and MNK2 and is in development for the 
treatment of advanced solid tumors and hematological malignancies. 
Tomivosertibwill be supplied as 100-mg capsules by the Sponsor. Capsules are packaged in 
200-cc high-density polyethylene wide-mouth, round, white bottles, at either 100 or 150 units per 
bottle, induction sealed and capped with a 38-mm child-resistant closure. 
 Manufacturing, Packaging, and Labeling 
Tomivosertib is manufactured according to current Good Manufacturing Practices. Tomivosertib 
will be packaged and labeled under the responsibility of the Sponsor and will comply with all 
applicable federal and local laws and regulations. Tomivosertib will be identified as an 
investigational product. 
No repackaging and/or relabeling activities at the study site are allowed. If the packaging is 
damaged, or if there is anything unusual about the appearance or attributes of the drug, it should 
not be used. The bottle in question should be saved at the study site and the problem immediately 
reported to the Sponsor. 
 Site Storage 
Tomivosertib should be stored at room temperature at 20C to 25C (68F to 77F). Access to 
tomivosertib should be restricted to designated study personnel. 
 Home Storage 
The study site staff are responsible for providing patients with instructions on storing 
tomivosertib at home. 
 Dispensing 
A pharmacist or other qualified staff member will dispense the appropriate amount of 
tomivosertib capsules according to the dosing schedule. Sufficient capsules will be dispensed to 
the patient to permit at least 4 weeks of therapy unless current stability data indicate that drug 
should be dispensed at more frequent intervals. For tomivosertib doses that are taken at the study 
site, patients will take the dose from the drug dispensed to them for that particular dispensing 
interval. All other tomivosertib doses will be taken at home. 


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 Compliance and Accountability 
The site must maintain accurate records including the dates and amount of tomivosertib received, 
lot numbers, to whom dispensed (patient by patient accounting), and accounts of any study drug 
accidentally or deliberately destroyed. 
Patients will be given an Instructions to Patient Sheet on which they will record the specific date 
and time they take their tomivosertib evening dose on the day before each study site visit. At 
each study visit, patients will return all bottles of tomivosertib (used and unused) along with the 
Instructions to Patient Sheet, and study staff will ask about their study drug compliance. The 
number of capsules returned should be counted and documented in the source documentation and 
in the eCRF for compliance. The date and time of dosing recorded in the Instructions to Patient 
Sheet and at each site visit should also be recorded in the eCRF. 
Empty, partially used, or full bottles of tomivosertib should be retained for review by the site 
monitor prior to return to the Sponsor or destruction. 
 Tomivosertib Disposal or Return 
After accountability has been verified, the site will return or destroy unused tomivosertib 
capsules as instructed by the Sponsor. 
If any study drug is to be destroyed at the site, the site must obtain prior approval by the Sponsor. 
After such destruction, the site must notify the Sponsor, in writing, of the method of destruction, 
the date of destruction, and the location of destruction. 
 Tomivosertib Administration 
Patients should take their assigned dose of tomivosertib PO BID at 12-hour intervals (2 hours). 
At all site visits, tomivosertib will be administered at the site with dosing appropriately timed 
(predose) relative to blood sampling for pharmacodynamic and PK assessments. On these visits, 
the site should record the exact time of the tomivosertib administration. All other doses should be 
taken at home. If a patient mistakenly takes tomivosertib at home on days when it should be 
administered at the site for PK sampling, blood samples for tomivosertib PK should not be 
collected on those days, and the patient should return at the next available time for tomivosertib 
administration at the clinical site for tomivosertib PK sampling.  
Patients should take tomivosertib while fasting (defined as no food with the exception of clear 
liquids for 2 hours before dosing and at least 1 hour after dosing).  
Because there is the potential that neutralization of gastric acidity may decrease drug absorption, 
patients are strongly advised to avoid the use of proton pump inhibitors (eg, dexlansoprazole, 
esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) and histamine H2 blockers 
(eg, cimetidine, famotidine, nizatidine, ranitidine) for 14 days prior to the first dose of 
tomivosertib and throughout the study. Patients should also avoid the use of bicarbonate- or 
hydroxide-containing antacids (eg, Gaviscon, Gelusil, Maalox, Milk of Magnesia, Mylanta, 
Rolaids, Tums) for 2 hours before and at least 1 hour after taking tomivosertib. 


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 Tomivosertib Dose Schedule Interruptions and Vomited Doses 
Patients who have a delay in taking a dose of tomivosertib of <6 hours should take the planned 
dose as soon as possible. If the delay is 6 hours, the dose should not be taken. The planned 
timing of subsequent tomivosertib dosing should not be altered. 
If a patient vomits shortly after taking tomivosertib, the vomited dose should not be replaced. 
The planned timing of subsequent tomivosertib dosing should not be altered. 
 Tomivosertib Dose Modifications for Drug-Related Toxicity 
If a patient experiences toxicity during a cycle, dose administration may be interrupted, and the 
patient should be monitored frequently until the event returns to baseline status or stabilizes. 
Treatment may be resumed at the same dose or reduced to a dose of 100 mg BID (Table 1) if the 
toxicity resolves to baseline status or ≤ Grade 1 within 14 days of onset and the perceived benefit 
of continued treatment outweighs the risk. Treatment at the next lower dose level of 100 mg QD 
may be resumed after discussion with the Sponsor. 
Patients should resume study treatment with tomivosertib within 14 days of the dose interruption, 
unless otherwise discussed with the Sponsor. The reason for interruption should be documented 
in the patient’s study record. If interruption was due to a toxicity that has not resolved to a level 
that would allow continuation of therapy, there should be a discussion with the Sponsor whether 
to continue observation until recovery or whether treatment should be discontinued. 
 


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Table 1: Dose-Modification Guidelines for Tomivosertib-Related Treatment-Emergent Adverse Events 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non 
hematological 
(except 
alopecia and 
reversible 
electrolyte 
disturbances)  
Continue at 
same dose 
level. 
Continue at same dose 
level or withhold dose 
until toxicity has resolved 
to ≤Grade 1 or has 
returned to baseline, then 
resume at same dose level. 
Withhold dose until resolution to 
≤Grade 1, then continue at same 
dose level at Investigator discretion 
or discuss dose reduction with 
Sponsor*. For hepatic toxicities, 
resolution to baseline/normal range 
is required prior to restarting study 
drug at 1 dose level lower. 
Rash, nausea, vomiting, or diarrhea 
must be G3 despite maximal medical 
therapy prior to dose hold. 
Withhold dose until resolution to 
≤Grade 1; for hepatic toxicities 
resolution to baseline/normal range 
is required. Discuss resuming study 
drug treatment at lower dose with 
Sponsor*.  
Rash, nausea, vomiting, or diarrhea 
must be G4 despite maximal medical 
therapy prior to dose hold. 
Hematological 
Continue at 
same dose 
level. 
Continue at same dose 
level or withhold dose 
until toxicity has resolved 
to ≤Grade 1 or has 
returned to baseline, then 
resume at same dose level. 
Withhold dose until resolution to 
≤Grade 1. Then continue at same 
dose level at Investigator discretion 
or discuss dose reduction with 
Sponsor*. 
Withhold dose until resolution to 
≤Grade 1. Discuss resuming study 
drug treatment at lower dose with 
Sponsor*.  
*Next level for dose reduction of tomivosertib is 100 mg BID. 
 


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6 CONCOMITANT THERAPIES, SUPPORTIVE CARE, AND OTHER 
CONSIDERATIONS 
 Concomitant Therapies 
 Acceptable Concomitant Medications and Procedures 
All treatments that the Investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. 
Palliative and supportive care is permitted during the study for underlying medical conditions 
and management of symptoms. Palliative radiotherapy is permitted if considered medically 
necessary by the Investigator; however, this will generally be considered indicative of 
progressive disease. It is recommended that tomivosertib treatment be stopped 1 week prior to 
radiotherapy and withheld during the period of irradiation and 1 week thereafter for resolution of 
any radiation-related toxicities. The Sponsor must be notified if palliative radiotherapy is started.  
Elective surgery (eg, cataract removal) for reasons other than management of the cancer is 
permitted. It is recommended to stop tomivosertib treatment 1 week prior to elective surgery; 
please discuss with the Sponsor prior to scheduling of these procedures. Postoperatively, the 
decision to reinitiate treatment with tomivosertib should be based upon clinical assessment of 
satisfactory wound healing and recovery from surgery. 
The specifics of the radiation treatment and surgery, including the location, will be recorded in 
the eCRF. 
 Prohibited Concomitant Medications and/or Treatments 
Patients are prohibited from receiving the following therapies during the study: 
• Chemotherapy and/or any other anticancer therapy 
• Investigational products other than tomivosertib 
• Surgery for cancer symptom management or tumor control 
• Radiation therapy for tumor control (palliative radiation is permitted; see Section 6.1.1) 
• Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest (such as cerebral metastases) or for use as a premedication in patients 
with a known history of an IV contrast allergy administered as part of CT radiography. 
Replacement doses of steroids (eg, prednisone 5 to 10 mg daily) are permitted while on 
study. 
• Bisphosphonates and/or RANKL inhibitor therapies cannot be initiated within 4 weeks of 
signing the Informed Consent Document(s).  
• Prophylactic antidiarrheals before the first dose of study drug on Cycle 1 Day 1  
• Prophylactic antiemetics before the first dose of study drug on Cycle 1 Day 1  


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• Prophylactic use of colony-stimulating factors (including granulocyte colony-stimulating 
factor [G-CSF], pegylated G-CSF, or granulocyte-macrophage colony-stimulating factor) 
is not allowed in this study prior to the first dose of therapy.  
Antidiarrheals, antiemetics and CSF therapies are permitted after an AE is seen. 
Start of anticoagulants such as warfarin is permitted after discussion with Sponsor. 
Patients may receive other medications that the Investigator deems to be medically necessary. 
The exclusion criteria describe other medications which are prohibited in this study 
(see Section 4.1.2). There are no prohibited therapies during the Post-Treatment Follow-Up 
Period. 
Although not prohibited, patients are strongly advised to avoid the use of proton pump inhibitors 
(eg, dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) and 
histamine H2 blockers (eg, cimetidine, famotidine, nizatidine, ranitidine) for 14 days prior to the 
first dose of tomivosertib and throughout the study. Patients should also avoid the use of 
bicarbonate- or hydroxide-containing antacids (eg, Gaviscon, Gelusil, Maalox, Milk of 
Magnesia, Mylanta, Rolaids, Tums) for 2 hours before and at least 1 hour after taking 
tomivosertib. 
 Rescue Medication and Supportive Care 
 General Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator including, but not limited to, the items outlined below. For guidelines for continuing 
treatment with study drug in the event of toxicity, see Section 5.1.10. 
• Anemia: Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia.  
• Anti-infectives: Patients with a documented infectious complication should receive oral 
or intravenous (IV) antibiotics or other anti-infective agents as considered appropriate by 
the treating Investigator for a given infectious condition, according to standard 
institutional practice. 
• Antidiarrheals may not be administered prophylactically before initial study 
administration on Cycle 1 Day 1. Thereafter, patients experiencing diarrhea (and/or 
abdominal cramping) following study drug administration may take loperamide at the 
earliest sign of a loose stool, an increase in bowel movements by 1 to 2 episodes 
compared to baseline, or an increase in stool volume or liquidity. The recommended 
regimen is 4 mg at the first onset of diarrhea, then 2 mg with each succeeding diarrheal 
stool until the patient is diarrhea-free for at least 12 hours. Additional antidiarrheal 
measures may be implemented at the discretion of the Investigator. Patients should also 
be instructed to maintain oral fluid intake to help sustain fluid and electrolyte balance 
during episodes of diarrhea. 
• Neutropenia: Therapeutic use of G-CSF is allowed in patients with Grade 3 to 4 febrile 
neutropenia.  


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• Thrombocytopenia: Transfusion of platelets may be used if clinically indicated. 
Idiopathic thrombocytopenic purpura should be ruled out before initiation of platelet 
transfusion. 
• Vomiting: After Cycle 1 Day 1, patients experiencing nausea or vomiting may be 
administered prophylactic or therapeutic antiemetics. It is recommended but not 
mandated that patients be offered 2 mg of granisetron as an oral tablet or solution every 
6 hours as needed or ondansetron as an oral tablet or solution every 8 hours as needed. If 
patients have persistent nausea or vomiting, consideration can be given to application of a 
31.3 mg granisetron transdermal patch every 3 to 7 days. For transdermal prophylaxis, 
24 to 48 hours may be necessary to allow a sufficient period to achieve effective 
granisetron systemic concentrations. Other oral serotonin antagonists (eg, dolasetron) 
may be substituted, if necessary. Other classes of antiemetic medications that may be 
employed include dopamine antagonists or benzodiazepines. The use of systemic 
corticosteroids (eg, dexamethasone) should be minimized to avoid immunocompromise; 
however, corticosteroids can be introduced if other types of antiemetic agents are not 
sufficiently effective. 
• Overdose: For this protocol, an overdose of tomivosertib is defined as a daily dose more 
than 25% of the dose assigned for that patient. In a patient who experiences an overdose, 
consideration should be given as to whether tomivosertib administration should be 
temporarily interrupted. If the overdose is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be 
considered. Observation for any symptomatic side effects should be instituted, and safety 
laboratory parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects 
should be initiated. The occurrence of an overdose does not preclude further protocol 
therapy as long as the patient appears to be safely benefiting from treatment and the 
circumstances that led to the initial overdose are unlikely to recur. 
 Other Considerations 
 Contraception 
Sexually active male patients who can father a child must agree to use a protocol-recommended 
method of contraception or to abstain from heterosexual intercourse with females of childbearing 
potential from the start of study drug until at least 30 days after the last dose of study drug. They 
must also refrain from sperm donation from the start of study drug until at least 90 days after the 
last dose of study drug. 
Protocol-recommended methods of contraception for study participants and female partners are 
listed in Table 2. 


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Table 2: Protocol-Recommended Contraception Methods for Study Participants and 
Female Partners 
Individual Methods 
Combination Methods 
Hormonal Methods 
(One method to be used  
with a barrier method) 
Barrier Methods 
(Both methods to be used OR one 
method to be used with one 
hormonal method) 
IUD (eg, Copper T380A, LNg20) 
Estrogen and progesterone 
Diaphragm with spermicide 
Tubal sterilization 
Oral contraceptives 
Male condom (with spermicide) 
Hysterectomy 
Transdermal patch 
 
Vasectomy 
Vaginal ring 
 
 
Progesterone 
 
 
Injection 
 
 
Implant 
 
Abbreviations: IUD, intrauterine device. 
In the context of this protocol, a male patient is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. 
 Diet 
Patients should be encouraged to follow instructions to fast (with the exception of clear liquids) 
for 2 hours before and at least 1 hour after each tomivosertib dose. Patients should be advised to 
avoid ingestion of grapefruit, grapefruit juice, or Seville orange juice (which contains a potent 
CYP3A4 inhibitor) and should not use St. John’s wort, which is a potent CYP3A4 inducer. No 
other specific dietary restrictions are required. 


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7 STUDY PROCEDURES AND ASSESSMENTS 
Prior to conducting any study-related activities, written informed consent and any other 
authorizations must be signed and dated by the patient or patient’s legal representative. 
Assessments that have been performed as part of standard care, prior to obtaining informed 
consent AND that are within 28 days of first dose of study drug, may be used for screening. 
Scans performed as part of routine clinical management are acceptable for use as baseline tumor 
imaging if they are of diagnostic quality and were performed within 7 days prior to the 28-day 
screening window.   
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time, there may be 
circumstances outside of the control of the investigator that may make it unfeasible to perform 
the test. In those cases, the investigator should take all steps necessary to ensure the safety and 
wellbeing of the patient. When a protocol-required test cannot be performed, the investigator will 
document the reason for this and any corrective and preventive actions which he/she has taken to 
ensure that normal processes are adhered to as soon as possible. The Sponsor study team should 
be informed of these incidents in a timely fashion. 
The following sections describe the study procedures and assessments to be performed during 
the study. See Section 8 and the Schedule of Events table for the timing of each activity. 
 Medical History, Demographics, and Prior and Concomitant 
Medications and Therapies 
 Medical History 
A complete medical history will be obtained to ensure patients qualify for the study. Medical 
history will be obtained through patient interview. A review of the patient’s medical records 
from their primary care physician is not required. Data collected will include the patient’s cancer 
history, previous anticancer therapies (including prior hormonal interventions), surgical history, 
past and ongoing medical conditions, and review of systems. 
 Demographics 
Demographic information collected will include age, sex, race, and ethnicity. 
 Genetic Markers 
Genetic testing will be performed on blood samples collected at screening or Cycle 1 Day 1 prior 
to first dose of tomivosertib to test for the absence or presence of relevant oncogenic mutations 
including, but not limited to, AR, ETS, TP53, and PTEN.  
 Prior and Concomitant Medications and Therapies 
Prior medications will be recorded at Screening only. All medications taken by patients between 
signing the Informed Consent Document(s) and the End-of-Treatment Visit will be recorded. 
Thereafter, only concomitant medications taken for the treatment of an AE will be recorded for 
up to 30 days after the last dose of study drug. 


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Concomitant medications include all prescription, over-the-counter, illicit, IV infusions, 
transfusions, and alternative medications (including herbal products and vitamins). For patients 
entering on a stable dose of permitted medication, any change in dose should also be recorded. 
Concomitant therapy (eg, radiation therapy) and surgery must also be recorded. 
If a patient takes a bicarbonate- or hydroxide-containing antacid (eg, Gaviscon, Gelusil, Maalox, 
Milk of Magnesia, Mylanta, Rolaids, Tums) on a study visit with PK assessments, the time the 
medication was taken should also be recorded. Patients should avoid the use of proton pump 
inhibitors (eg, dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, 
rabeprazole) and histamine H2 blockers (eg, cimetidine, famotidine, nizatidine, ranitidine) for 
14 days prior to the first dose of tomivosertib and throughout the study; however, if any of these 
medications are taken prior to or during treatment, these medications must be recorded on the 
eCRF, including the drug name, dose, and date of administration. 
 Safety Assessments 
 Adverse Events 
All AEs, regardless of causality or seriousness, will be recorded from the time the patient takes 
the first dose of study drug until 30 days after the last dose of study drug. After discontinuing 
study drug, patients will be followed until the later of either 30 days after the last dose of study 
drug or until resolution/stabilization of any ongoing drug-related AEs. This follow-up may be 
obtained in person or by telephone contact. See Section 9 for more details on recording and 
reporting AEs. Adverse events will be assessed at every clinic visit per protocol. 
 Physical Examination/Assessment 
A physical examination is required at Screening and Cycle 1 Day 1 that will include an 
evaluation of cardiovascular, respiratory, GI, neurological, dermatological, and musculoskeletal 
systems. Thereafter a physical assessment, which can be done by a research nurse, may be 
performed. Weight will be measured at each physical examination/assessment. Height will only 
be measured at Screening. Clinically significant physical examination/assessment findings after 
initiating tomivosertib should be recorded as AEs. 
 Vital Signs 
Vital signs should be taken before dosing and include systolic and diastolic blood pressure, 
pulse, and temperature on scheduled visit days. Patients should be in a supine position (includes 
sitting in a recliner chair) for at least 5 minutes before taking vital signs. Clinically significant 
vital sign results after initiating study drug should be recorded as AEs. 
 12-Lead Electrocardiograms 
Standard digital 12-lead ECGs will be performed at screening and Day 1 of each cycle. Patients 
should be in the supine position (includes sitting in a recliner chair) for at least 5 minutes before 
each ECG recording. ECG parameters include ventricular rate, QRS, PR, and QT intervals; and 
QT interval corrected using Fridericia’s formula. The results will be reviewed by the 
Investigator. Any ECG finding that is judged by the investigator as a clinically significant 


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change (worsening) compared with a baseline value will be considered an AE and must be 
recorded in the eCRF. 
 Local Laboratory Assessments 
Blood and urine samples will be collected for diagnostic screening tests and for safety laboratory 
tests (hematology, serum chemistry, coagulation, and urinalysis). See Table 3 for a list of 
diagnostic and safety laboratory tests and parameters. Testing will be performed by Clinical 
Laboratory Improvement Amendments (CLIA)-certified laboratories associated with the study 
sites. 
On tomivosertib clinic dosing days, predose samples should be obtained and results assessed 
before tomivosertib administration. 
Laboratory results will be reviewed by the Investigator. Any laboratory values outside of the 
normal reference range will be evaluated for clinical significance. Clinically significant findings 
after initiating study drug will be recorded as AEs. 
Refer to the Study Laboratory Manual for detailed instructions on sample collection, processing, 
and shipping procedures. 
Table 3: Diagnostic and Safety Laboratory Tests and Parameters 
Laboratory Test 
Parameters 
Serum chemistry 
Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, 
phosphorus, magnesium, total protein, albumin, ALT, AST, ALP, CK, LDH, 
total bilirubin, uric acid, 
Serum testosterone to be confirmed at baseline as ≤1.73 nmol/L (50 ng/dL) 
Hematology 
Hematocrit, hemoglobin, erythrocyte count 
Absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils 
Platelet count 
Coagulation 
PT, aPTT, INR 
Urinalysis 
Dipstick: specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, 
blood, nitrite, leukocyte esterase 
Microscopy: white blood cells, red blood cells, epithelial cells, bacteria, casts, 
crystals (to be performed as needed) 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, 
aspartate aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; INR, international normalized ratio; LDH, lactate 
dehydrogenase; PT, prothrombin time.  
 Eastern Cooperative Oncology Group Performance Status 
ECOG performance status will be assessed at Screening, Day 1 of every cycle, and at the End-of-
Treatment Visit to measure how the disease impacts a patient’s daily living abilities. The ECOG 
performance status scale assesses the patient’s level of functioning in terms of their ability to 
care for him/herself, daily activity, and physical ability (Oken 1982). See Appendix 13.3. 


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 Efficacy Assessments 
 Prostate-specific Antigen  
PSA levels will be assessed locally at Screening, on Day 1 of every cycle, and at end of 
treatment.  
Tumor response will be evaluated using PSA levels as a co-primary endpoint. A patient will be 
considered a responder if a ≥50% decline from baseline in PSA level is observed at any 
postbaseline time point and maintained for ≥4 weeks. 
A secondary efficacy endpoint is PCWG2 PSA progression-free survival (PSA progression 
defined as a ≥25% increase in PSA from nadir or baseline [and by ≥2 ng/mL] and requiring 
confirmation ≥3 weeks later). Both of these endpoints are further described in Section 10.4.5.1. 
PSA flare is characterized by a rise in the PSA level after starting therapies such as androgen 
deprivation therapy, systemic chemotherapy, or local therapies such as brachytherapy or 
cryotherapy, followed by a decline to below baseline values as defined by PSA level values 
recorded before starting therapy for prostate cancer. PSA flare is not considered to be disease 
progression. In the event of PSA flare, treatment with tomivosertib should continue. PSA 
progression will occur when a patient has a second value ( ≥25% and ≥2 ng/mL above the nadir) 
3 or more weeks after the first increase in PSA to confirm the rising trend. 
PCWG2 recommends continuing treatment with newly initiated prostate cancer therapies for at 
least 12 weeks without clinical evidence for disease progression. It is recommended that study 
treatment not be discontinued early in its treatment course if an asymptomatic PSA rise occurs. 
 Radiology Examination  
Disease will also be assessed using radiology examination. Radiology examination will include 
CT (and may include positron emission tomography (PET), if relevant) or magnetic resonance 
imaging (MRI) imaging of chest, abdomen, and pelvis. The same method of assessment (CT, 
CT/PET, MRI) and the same technique should be used to characterize each identified and 
reported lesion at Screening and while on study. Evaluations are to be performed during 
Screening within 28 days prior to the initiation of study treatment (scans performed as part of 
routine clinical management are acceptable for use as baseline tumor imaging if they are of 
diagnostic quality and were performed within 7 days prior to the 28-day screening window), then 
every 8 ± 1 weeks for 1 year, then every 12 ± 1 weeks. Care must be taken in scheduling disease 
assessments to prevent introduction of bias based on treatment delays. An end-of-treatment 
radiology assessment should be performed unless the patient already has radiographic 
confirmation of PD ≤4 weeks prior to permanent study drug discontinuation. 
Disease response will be evaluated using iRECIST objective response as a co-primary endpoint. 
Investigators should consider all target and nontarget lesions when determining whether tumor 
burden has increased or decreased. See Appendix 13.6 for information on methods of evaluation 
as well as tumor response and progression criteria.  
A secondary efficacy endpoint based on iRECIST criteria is progression-free survival (iPFS). 
iRECIST endpoints are described in Section 10.4.5.1. 


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 Bone Scan 
Bone scans will be performed using standard local radionuclide imaging. The same technique 
should be used to evaluate the presence of bone lesions during screening and throughout the 
study.  
Bone scans will be performed at screening every 8 ± 1 weeks for 1 year, then every 12 ± 1 weeks 
until progression. New bone lesions are to be confirmed with repeat scan 6 or more weeks later.  
A secondary efficacy endpoint is bone PFS as defined by PCWG2. Patients are considered to 
have bone progression when two or more new lesions are detected on a post-baseline bone scan 
and the confirmatory scan shows additional new lesions compared to the previous scan. 
Additional details regarding this endpoint are described in Section 10.4.5.1. 
 
Determining Disease Progression 
Patients with disease progression who have potential for clinical benefit in the opinion of the 
Investigator may continue to receive study drug until progression is confirmed per 
iRECIST/PCWG2 PSA/bone scan criteria at the next scan or they are no longer having benefit. 
Clinical stability is defined as follows: 
• Absence of clinical signs and symptoms (including worsening of laboratory values) of 
disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease by radiographic imaging 
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
If repeat imaging no longer shows PD, but instead shows complete response (CR), partial 
response (PR), or stable disease compared with the initial scan, study drug may be 
continued/resumed. 
If the repeat imaging confirms PD, study drug discontinuation should be considered unless the 
patient is considered to be deriving clinical benefit, in the opinion of the Investigator, and is 
clinically stable. See Section 4.4.1 for more information on determining if a patient should 
discontinue therapy. 
At the discretion of the Investigator and with the Sponsor’s approval, patients who meet PSA 
progression criteria per PCWG2 may continue treatment with tomivosertib if the patient is 
perceived to be deriving clinical benefit. 
 Pharmacokinetics Analysis 
Blood samples will be collected to determine the PK plasma concentration of tomivosertib. PK 
analyses will be performed at the contracted Good Laboratory Practice laboratories as designated 
by the Sponsor. Please refer to the study laboratory manual for detailed instructions on sample 
collection, processing, storage, and shipping procedures.  


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 Exploratory Assessments 
 Circulating Tumor Cells 
CTCs will be assessed in blood collected at Screening or Cycle 1 Day 1 prior to first dose of 
tomivosertib, Day 1 of every cycle, and at the end of treatment using the Oncotype DX AR-V7 
Nucleus Detect Test. Please refer to the study laboratory manual for detailed instructions. 
 P-eIF4E 
Tumor tissue (archival or fresh), if available will be obtained at Screening to evaluate P-eIF4E 
status. Baseline archival tumor tissue if available should be from a biopsy procedure performed 
closest to the start of study treatment. If archival tissue is unavailable, tissue sample from a fresh 
biopsy may be submitted, if patient agrees to the this optional procedure. Please refer to the study 
laboratory manual for detailed instructions. 
 


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8 SCHEDULE OF EVENTS 
This section lists the study procedures and assessments that will be performed at scheduled time 
points during the study. See Section 7 for information on study procedures and assessments. 
Unless there is a safety concern, every effort should be made to avoid protocol deviations. 
Additional visits and/or assessments are permitted if clinically indicated in the opinion of the 
Investigator. 
When the following assessments are scheduled at the same time point, it is recommended that 
they be performed in this order: vital signs, 12-lead ECG, and blood sample collection. 
 
 


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 Screening Period 
At the start of the Screening Period, prospective study patients will be fully informed about the 
nature of the study and possible risks. Patients must read and sign the Informed Consent 
Document(s) after the Investigator has answered all questions to the patient’s satisfaction. 
After obtaining informed consent, patients will undergo Screening procedures to confirm 
eligibility for study participation. Screening procedures must be performed within 28 days prior 
to initiating study drug. Assessments that have been performed as part of standard care, prior to 
obtaining informed consent AND that are within 28 days of first dose of study drug, may be used 
for screening. Scans performed as part of routine clinical management are acceptable for use as 
baseline tumor imaging if they are of diagnostic quality and were performed within 7 days prior 
to the 28-day screening window. 
The Investigator must evaluate the patient’s medical history and the results of all Screening 
assessments to determine study eligibility before the patient is enrolled. 
Assessment/Procedure 
Notes 
Reference Information 
Medical history 
 
Section 7.1.1 
Demographics 
 
Section 7.1.2 
Physical 
examination/assessment 
 
Section 7.3.2 
Height and weight 
 
Section 7.3.2 
ECOG performance 
status 
 
Section 7.3.6 and 
Appendix 13.3 
Vital signs  
 
Section 7.3.3 
12-lead ECG 
 
Section 7.3.4 
Blood sample for 
diagnostic and safety 
laboratory tests 
• Hematology  
• Serum chemistry  
• Coagulation 
• Serum testosterone 
Section 7.3.5, 
Section 7.4.1, and the 
Study Laboratory Manual 
Urinalysis 
 
Section 7.3.5 and the 
Study Laboratory Manual 
Blood sample for 
efficacy (PSA) 
PSA done locally by the site 
Section 7.4.1 
Blood sample for genetic 
markers 
May be performed at Cycle 1 Day 1 
Section 7.1.3 and the 
Study Laboratory Manual 
Blood sample for CTC  
 
Section 7.6.1 and the 
Study Laboratory Manual 
Optional Tumor tissue 
(archival or fresh) 
 
Section 7.6.2 and the 
Study Laboratory Manual 
Radiology examination, 
including bone scan 
• The preferred radiology examination methods are CT 
(and may include PET, if relevant) or MRI of the 
chest, abdomen, and pelvis 
• To be performed within 28 days prior to the initiation 
of study drug 
Section 7.4.2 
Prior and concomitant 
medication and therapy 
recording 
 
Section 7.2 
Abbreviations: CT, computed tomography; CTC, circulating tumor cells; ECG, electrocardiogram; ECOG, Eastern Cooperative 
Oncology Group; MRI, magnetic resonance imaging; PET, positron emission tomography; PSA, prostate-specific antigen. 


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 Treatment Period (4-Week [28-day]) Treatment Cycles) 
Patients will return to the site to complete study assessments at scheduled visits. At each study 
visit where blood is taken for PK, patients will take the morning tomivosertib dose at the site. All 
other tomivosertib doses will be taken at home. Patients will also record the time they take their 
tomivosertib evening dose the day before each study visit on the Instructions to Patient Sheet. A 
summary of study assessments and procedures by visit is outlined below. 
 Cycle 1 
8.2.1.1 Cycle 1 Day 1 
Assessment/Procedure 
Notes 
Reference Information 
Predose Activities  
Physical examination 
 
Section 7.3.2 
Weight 
 
Section 7.3.2 
ECOG performance status 
 
Section 7.3.6 and 
Appendix 13.3 
Vital signs  
 
Section 7.3.3 
12-lead ECG 
 
Section 7.3.4 
Blood sample for safety 
laboratory tests 
• Hematology  
• Serum chemistry 
Section 7.3.5 and the 
Study Laboratory Manual 
Urinalysis 
 
Section 7.3.5 and the 
Study Laboratory Manual 
Blood sample for tomivosertib 
PK[a] 
Collected prior to morning dose 
Section 7.5 and the Study 
Laboratory Manual 
Blood sample for PSA 
Collected prior to morning dose 
Section 7.4.1 and the 
Study Laboratory Manual 
Blood sample for CTC 
Collected prior to morning dose 
Section 7.6.1 and the 
Study Laboratory Manual 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Study Drug Administration  
Tomivosertib administration  
• Morning dose of tomivosertib to be 
administered at study site 
• Record time of dosing 
Section Error! 
Reference source not 
found. 
Dispensing of tomivosertib 
• Patients will be given an Instructions to 
Patient Sheet for recording the specific time of 
their last tomivosertib dose on the day before 
each study site visit.  
• At each study visit, patients will return all 
bottles of tomivosertib (used and unused) and 
the Instructions to Patient Sheet. 
Section 5.1.5 
Blood sample collection for 
tomivosertib PK[a] 
3 1 hours after tomivosertib morning dose 
Section 7.5 and the Study 
Laboratory Manual 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 


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Abbreviations: AE, adverse event; CTC, circulating tumor cells; ECG, electrocardiogram; ECOG, Eastern Cooperative 
Oncology Group; PK, pharmacokinetics; PSA, prostate-specific antigen. 
[a] The date and actual clock time of blood sampling must be recorded. 
 
8.2.1.2 Cycle 1 Day 8 (3 Days) 
Assessment/Procedure 
Notes 
Reference Information 
Predose Activities 
Tomivosertib return and 
compliance check 
• Empty, partially used, or full bottles of 
tomivosertib to be retrieved from the patient 
for drug compliance 
• Review Instructions to Patient Sheet for time 
tomivosertib evening dose was taken the day 
before 
Section 5.1.6 
Physical examination/ 
assessment[a] 
 
Section 7.3.2 
Weight 
 
Section 7.3.2 
Vital signs  
 
Section 7.3.3 
Blood sample for safety 
laboratory tests 
• Hematology  
• Serum chemistry 
Section 7.3.5 and the 
Study Laboratory Manual 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Study Drug Administration  
Tomivosertib administration  
• Record time of dosing 
Section Error! 
Reference source not 
found. 
Postdose Activities 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Abbreviations: AE, adverse event. 
[a] A physical assessment, which can be performed by a research nurse, may be done instead of a physical examination. 
 


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8.2.1.3 Cycle 1 Day 15 (3 Days) 
Assessment/Procedure 
Notes 
Reference Information 
Predose Activities 
Tomivosertib return and 
compliance check 
• Empty, partially used, or full bottles of 
tomivosertib to be retrieved from the patient 
for drug compliance 
• Review Instructions to Patient Sheet for time 
tomivosertib evening dose was taken the day 
before 
Section 5.1.6 
Physical examination/ 
assessment[a] 
 
Section 7.3.2 
Weight 
 
Section 7.3.2 
Vital signs  
 
Section 7.3.3 
Blood sample for safety 
laboratory tests 
• Hematology  
• Serum chemistry 
Section 7.3.5 and the 
Study Laboratory Manual 
Blood sample for tomivosertib 
PK[b]  
Collected prior to morning dose[c]  
Section 7.5 and the Study 
Laboratory Manual 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Study Drug Administration  
Tomivosertib administration  
• Morning dose of tomivosertib to be 
administered at study site 
• Record time of dosing 
Section Error! 
Reference source not 
found. 
Postdose Activities 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Blood sample for tomivosertib 
PK[b]  
3 1 hours after tomivosertib morning dose 
Section 7.5 and the Study 
Laboratory Manual 
Abbreviations: AE, adverse event; PK, pharmacokinetics. 
[a] A physical assessment, which can be performed by a research nurse, may be done instead of a physical examination. 
[b] The date and actual clock time of blood sampling must be recorded. If a patient mistakenly takes tomivosertib at home on 
days when it should be administered at the site for PK sampling, blood samples for tomivosertib PK should not be collected 
on those days, and the patient should return at the next available time for tomivosertib administration at the clinical site with 
tomivosertib PK sampling. 
[c] The predose sample should be obtained at 12 ± 1 hours postdose from the Cycle 1 Day 14 tomivosertib evening dose. The 
time of the tomivosertib Cycle 1 Day 14 evening dose administered at home, prior to PK blood collection, should also be 
recorded. 
 


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Cycle 2 
8.2.2.1 Cycle 2 Day 1 (3 Days) 
Assessment/Procedure 
Notes 
Reference Information 
Predose Activities 
Tomivosertib return and 
compliance check 
• Empty, partially used, or full bottles of 
tomivosertib to be retrieved from the patient for 
drug compliance 
• Review Instructions to Patient Sheet for time 
tomivosertib evening dose was taken the day 
before 
 
Section 5.1.6 
Physical examination/ 
assessment[a] 
 
Section 7.3.2 
Weight 
 
Section 7.3.2 
ECOG performance status 
 
Section 7.3.6 and 
Appendix 13.3 
Vital signs  
 
Section 7.3.3 
Blood sample for safety 
laboratory tests 
• Hematology  
• Serum chemistry 
Section 7.3.5 and the 
Study Laboratory Manual 
Blood sample for tomivosertib 
PK[b]  
Collected prior to morning dose[c]  
Section 7.5 and the Study 
Laboratory Manual 
Blood sample for PSA 
Collected prior to morning dose 
Section 7.4.1 and the 
Study Laboratory Manual 
Blood sample for CTC 
Collected prior to morning dose 
Section 7.6.1 and the 
Study Laboratory Manual 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Dispensing of tomivosertib 
 
Section 5.1.5 
Study Drug Administration  
Tomivosertib administration  
• Morning dose of tomivosertib to be administered 
at study site 
• Record time of dosing 
• Day 28 evening dose to be administered at home, 
prior to PK blood collection. Time should be 
recorded. 
Section Error! 
Reference source not 
found. 
Postdose Activities 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Blood sample for tomivosertib 
PK[b]  
3 1 hours after tomivosertib morning dose 
Section 7.5 and the Study 
Laboratory Manual 
Abbreviations: AE, adverse event; CTC, circulating tumor cells; ECOG, Eastern Cooperative Oncology Group; 
PK, pharmacokinetics; PSA, prostate-specific antigen 
[a] A physical assessment, which can be performed by a research nurse, may be done instead of a physical examination. 
[b] The date and actual clock time of blood sampling must be recorded. If a patient mistakenly takes tomivosertib at home on 
days when it should be administered at the site for PK sampling, blood samples for tomivosertib PK should not be collected 
on those days, and the patient should return at the next available time for tomivosertib administration at the clinical site with 
tomivosertib PK sampling. 


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[c] The predose sample should be obtained at 12 ± 1 hours postdose from the Cycle 1 Day 28 tomivosertib evening dose. The 
time of the tomivosertib Cycle 1 Day 28 evening dose administered at home, prior to PK blood collection, should also be 
recorded. 
 
8.2.2.2 Cycle 2 Day 8 (3 Days) 
Assessment/Procedure 
Notes 
Reference Information 
Predose Activities 
Tomivosertib return and 
compliance check 
• Empty, partially used, or full bottles of 
tomivosertib to be retrieved from the patient 
for drug compliance 
• Review Instructions to Patient Sheet for time 
tomivosertib evening dose was taken the day 
before 
Section 5.1.6 
Physical examination/ 
assessment[a] 
 
Section 7.3.2 
Weight 
 
Section 7.3.2 
Vital signs  
 
Section 7.3.3 
Blood sample for safety 
laboratory tests 
• Hematology  
• Serum chemistry 
Section 7.3.5 and the 
Study Laboratory Manual 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Study Drug Administration  
Tomivosertib administration  
• Record time of dosing 
Section Error! 
Reference source not 
found. 
Postdose Activities 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Abbreviations: AE, adverse event. 
[a] A physical assessment, which can be performed by a research nurse, may be done instead of a physical examination. 
 


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8.2.2.3 Cycle 2 Day 15 (3 Days) 
Assessment/Procedure 
Notes 
Reference Information 
Predose Activities 
tomivosertib return and 
compliance check 
• Empty, partially used, or full bottles of 
tomivosertibto be retrieved from the patient for 
drug compliance 
• Review Instructions to Patient Sheet for time 
tomivosertib evening dose was taken the day 
before 
Section 5.1.6 
Blood sample for safety 
laboratory tests 
• Hematology  
• Serum chemistry 
Section 7.3.5 and the 
Study Laboratory Manual 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Study Drug Administration  
Tomivosertib administration  
• Record time of dosing 
Section Error! 
Reference source not 
found. 
Postdose Activities 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Abbreviations: AE, adverse event. 
 
 
Cycle 3 Day 1 (3 Days) 
Patients should have a radiology examination performed every 8 1 weeks from initiation of 
Cycle 1 Day 1 for 1 year, then every 12 1 weeks until PD or death. The Investigator should 
review the results, and patients who have not progressed, as defined by iRECIST will be eligible 
to start the next treatment cycle. Patients with disease progression who have potential for clinical 
benefit in the opinion of the Investigator may continue to receive study drug until progression is 
confirmed per iRECIST at the next scan or they are no longer having benefit (see Section 7.4.4 
for more information on assessing PD).  


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Study procedures and assessments to be performed on Day 1 of Cycle 3 onwards are as follows: 
Assessment/Procedure 
Notes 
Reference Information 
Predose Activities 
Tomivosertib return and 
compliance check 
• Empty, partially used, or full bottles of 
tomivosertib to be retrieved from the 
patient for drug compliance 
Review Instructions to Patient Sheet for time 
tomivosertib evening dose was taken the 
day before 
Section 5.1.6 
Physical examination/ assessment[a] 
 
Section 7.3.2 
Weight 
 
Section 7.3.2 
ECOG performance status 
 
Section 7.3.6 and 
Appendix 13.3 
Vital signs  
 
Section 7.3.3 
12-lead ECG 
 
Section 7.3.4 
Blood sample for safety laboratory 
tests 
• Hematology  
• Serum chemistry 
Section 7.3.5 and the 
Study Laboratory Manual 
Urinalysis 
Performed at Cycle 3 and every other cycle 
thereafter 
Section 7.3.5 
Blood sample for tomivosertib 
PK[b]  
At Cycles 4 and 8 only, collected prior to 
morning dose[c]  
Section 7.5 and the Study 
Laboratory Manual 
Blood sample for PSA 
Collected prior to morning dose 
Section 7.4.1 and the 
Study Laboratory Manual 
Blood sample for CTC 
Collected prior to morning dose 
Section 7.6.1 and the 
Study Laboratory Manual 
Radiology examination, including 
bone scan 
The preferred radiology examination methods 
are CT (and may include PET, if relevant) or 
MRI of the chest, abdomen, and pelvis 
Section 7.4 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Dispensing of tomivosertib 
 
Section 5.1.5 
Study Drug Administration  
Tomivosertib administration  
• Morning dose of tomivosertib to be 
administered at study site 
• Record time of dosing 
 
Section Error! 
Reference source not 
found. 
Postdose Activities 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Blood sample for tomivosertib PK[a]  3 1 hours after tomivosertib morning dose 
Section 7.5 and the Study 
Laboratory Manual 
Abbreviations: AE, adverse event; CTC, circulating tumor cells; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology 
Group; PK, pharmacokinetics; PSA, prostate-specific antigen 
[a] A physical assessment, which can be performed by a research nurse, may be done instead of a physical examination. 
[b] The date and actual clock time of blood sampling must be recorded. If a patient mistakenly takes tomivosertib at home on 
days when it should be administered at the site for PK sampling, blood samples for tomivosertib PK should not be collected 
on those days, and the patient should return at the next available time for tomivosertib administration at the clinical site with 
tomivosertib PK sampling. 
[c] Cycle 4 Day 1 and Cycle 8 Day. To be obtained at 12 ± 1 hours postdose from the Cycle 3 Day 28 and Cycle 7 Day 28 
tomivosertib evening doses. The time of the tomivosertib Cycle 3 Day 28 and Cycle 7 Day 28 evening doses administered at 
home, prior to PK blood collection, should also be recorded. 


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Radiologic Examinations 
Disease assessments using radiology examinations will be performed during Screening within 
28 days prior to the initiation of study therapy; then every 8 ± 1 weeks for 1 year, then every 
12 ± 1 weeks. An end-of-treatment radiology assessment should be performed unless the patient 
already has radiographic confirmation of PD ≤4 weeks prior to permanent study drug 
discontinuation. See Section 7.4.2. 
Bone scans will be performed every 8 ± 1 weeks for 1 year, then every 12 ± 1 weeks until 
progression. New bone lesions are to be confirmed with repeat scan 6 or more weeks later. See 
Section 7.4.3. 
 
End-of-Treatment Visit (+14 Days) 
Patients who discontinue study drug should complete the End-of-Treatment procedures and 
assessments summarized below: 
Assessment/Procedure 
Notes 
Reference Information 
Tomivosertib return and 
compliance check 
• Empty, partially used, or full bottles of 
tomivosertib to be retrieved from the patient 
for drug compliance 
Review Instructions to Patient Sheet for time 
tomivosertib evening dose was taken the day 
before 
Section 5.1.6 
Physical examination/ 
assessment[a] 
 
Section 7.3.2 
Weight 
 
Section 7.3.2 
ECOG performance status 
 
Section 7.3.6 and 
Appendix 13.3 
Vital signs  
 
Section 7.3.3 
12-lead ECG 
 
Section 7.3.4 
Blood sample for safety 
laboratory tests 
• 
Hematology 
• 
Serum chemistry 
• 
Coagulation 
Section 7.3.5 and the 
Study Laboratory Manual 
Blood sample for PSA 
Collected prior to morning dose 
Section 7.4.1 and the 
Study Laboratory Manual 
Blood sample for CTC 
Collected prior to morning dose 
Section 7.6.1 and the 
Study Laboratory Manual 
Urinalysis 
 
Section 7.3.5 
AE recording 
 
Section 7.3.1 and 
Section 9 
Concomitant medication and 
therapy recording 
 
Section 7.2 
Radiology examination, 
including bone scan 
Not required if patient had radiographic 
confirmation of PD 4 weeks prior to 
discontinuing study drug 
Section 7.4 and 
Section 7.4.3 
Abbreviations: AE, adverse event; CTC, circulating tumor cells; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology 
Group; PD, progressive disease; PSA, prostate-specific antigen 
[a] A physical assessment, which can be performed by a research nurse, may be done instead of a physical examination. 
 


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 Post-Treatment Follow-Up Period 
 30-Day Follow-Up 
Post-treatment safety assessment will be performed after permanent cessation of tomivosertib to 
follow patients for any drug-related AEs and/or ongoing serious adverse events (SAEs). Patients 
will be followed for ≥30 days or until those events have resolved or become stable, whichever 
occurs later. Follow-up may be obtained in person or by telephone contact. 
 Long-Term Follow-Up 
Long-term follow-up information will be obtained in all surviving patients who permanently 
discontinue study therapy. Data on the first post-study therapy for the cancer and on survival will 
be collected. Such information may be collected at ~3- to 6-month intervals at the Sponsor’s 
discretion through 18 months or death, whichever occurs first. This long-term follow-up 
information will be gathered during routine clinic visits, other study site contact with the 
patients, or via telephone or e-mail with the patients/caregivers or referring physician offices. 
These data will be collected in the source documents (eg, patient medical record) and transcribed 
to a specific eCRF. 


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9 ADVERSE EVENT MONITORING 
 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and/or unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal 
product. All AEs, including observed or volunteered problems, complaints, or symptoms, are to 
be recorded on the appropriate eCRF. 
AEs, which include clinical laboratory test variables, will be monitored and documented from 
the time the patient takes the first dose of study drug until 30 days after the last dose of study 
drug. Patients should be instructed to report any AE that they experience to the Investigator. Any 
AEs identified after signing of ICF and prior to first dose should be captured as updated medical 
history. Starting from first dose, Investigators should make an assessment for AEs at each visit 
and record the event on the appropriate AE eCRF. 
Wherever possible, a diagnosis (if known) should be recorded on the Adverse Event eCRF rather 
than individual signs and symptoms (eg, record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if an observed or reported sign or 
symptom is not considered a component of a specific disease or syndrome by the Investigator, it 
should be recorded as a separate AE on the eCRF. Additionally, the condition that led to a 
medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, transfusion) should be 
recorded as an AE, not the procedure. 
Any medical condition, other than the patient’s underlying cancer, already present at Screening 
should not be reported as an AE unless the medical condition or signs or symptoms present at 
Screening change in severity or seriousness at any time during the study. In this case, it should 
be reported as an AE. 
Clinically significant abnormal laboratory or other examination (eg, ECG) findings that are 
detected during the study or are present at Screening and significantly worsen during the study 
should be reported as AEs. If a clinically significant laboratory abnormality is a sign of a disease 
or syndrome (eg, increased alkaline phosphatase and bilirubin at 5  ULN associated with 
cholestasis), only the diagnosis (ie, cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating if the test result is above or below the normal range (eg, “elevated potassium,” as 
opposed to “abnormal potassium”). If the laboratory abnormality can be characterized by a 
precise clinical term per standard definitions, the clinical term should be recorded as the AE. For 
example, an elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
The Investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. Clinically 
significant abnormal laboratory values occurring during the clinical study will be followed until 
repeat tests return to normal, stabilize, or are no longer clinically significant. Any abnormal test 
that is determined to be an error does not require reporting as an AE. 


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Disease progression or events related to disease progression will be not captured as an AE/ SAE 
unless resulting in death. 
 Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an AE is at least a reasonable possibility; ie, the 
relationship cannot be ruled out. 
 Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For tomivosertib, the reference 
safety information is included in the IB currently in force. The reference safety information will 
be reviewed yearly and the periodicity of the review will be harmonized with the reporting 
period of the Development Safety Update Report. 
 Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to study drug using the categories of 
possibly related or unlikely related. 
Assessment of Severity: 
The severity of all AEs should be graded according to the NCI CTCAE Version 5. These criteria 
can be found at http://ctep.cancer.gov/reporting/ctc.html. For those AEs not listed in the CTCAE, 
the following grading system should be used: 
• Mild (CTCAE Grade 1): Transient symptoms, awareness of sign/symptom, but easily 
tolerated and no interference with patient’s daily activities. 
• Moderate (CTCAE Grade 2): Marked signs/symptoms that interfere with patient’s usual 
activities, but still acceptable. 
• Severe (CTCAE Grade 3): Incapacitating signs/symptoms which cause considerable 
interference with the patient’s daily activities, unacceptable. 
• Life-threatening (CTCAE Grade 4): Life-threatening consequences; urgent intervention 
indicated. 
• Death (CTCAE Grade 5): Death-related AE. 
Causality Assessment: 
The relationship of an AE to the administration of tomivosertib is to be assessed according to the 
following definitions: 
• Possibly related – The AE is known to occur with the study drug, there is a reasonable 
possibility that the study drug caused the AE, or there is a temporal relationship between 
the study drug and event. Reasonable possibility means that there is evidence to suggest a 
causal relationship between the study drug and the AE. 


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• Unlikely related – There is not a reasonable possibility that the administration of the 
study drug caused the event, there is no temporal relationship between the study drug and 
event onset, or an alternate etiology has been established. 
The following factors should also be considered: 
• The temporal sequence from study drug administration - 
o The event should occur after the study drug is given. The length of time from 
study drug exposure to event should be evaluated in the clinical context of the 
event. 
• Underlying, concomitant, intercurrent diseases - 
o Each report should be evaluated in the context of the natural history and course of 
the disease being treated and any other disease the patient may have. 
• Concomitant drugs - 
o The other drugs the patient is taking or the treatment the patient receives should 
be examined to determine whether any of them might be recognized to cause the 
event in question. 
• Known response pattern for this class of study drug - 
o Clinical and/or preclinical data may indicate whether a particular response is 
likely to be a class effect.  
• Exposure to physical and/or mental stresses - 
o The exposure to stress might induce adverse changes in the recipient and provide 
a logical and better explanation for the event. 
• The pharmacology and PK of the study drug - 
o The known pharmacologic properties (absorption, distribution, metabolism, and 
excretion) of the study drug should be considered. 
 Serious Adverse Events 
An AE or adverse reaction is considered serious if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes: 
• Death. 
• A life-threatening AE 
o NOTE: An AE or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate 
risk of death. It does not include an event that, had it occurred in a more severe 
form, might have caused death. 
• Requires hospitalization or prolongation of existing hospitalizations 
o NOTE: Any hospital admission with at least 1 overnight stay will be considered 
an inpatient hospitalization. An emergency room visit without hospital admission 
will not be recorded as an SAE under this criterion, nor will hospitalization for a 


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procedure scheduled or planned before signing of informed consent. However, 
unexpected complications and/or prolongation of hospitalization that occur during 
elective surgery should be recorded as AEs and assessed for seriousness. 
Admission to the hospital for social or situational reasons (eg, no place to stay, 
live too far away to come for hospital visits) will not be considered inpatient 
hospitalizations. 
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• An important medical event 
o NOTE: Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalizations, or the development of 
drug dependency. 
 Serious Adverse Event Reporting − Procedures for Investigators 
All SAEs occurring from the time the patient takes the first dose of study drug until 30 days after 
the last dose of study drug must be reported to the Sponsor designee within 24 hours of the 
knowledge of the occurrence (this refers to any AE that meets any of the aforementioned serious 
criteria). All SAEs that the Investigator considers related to study drug occurring after the 30-day 
follow-up period must be reported to the Sponsor. 
Instructions and contact details to report a safety event or an SAE are provided in the Study 
Reference Manual.  
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
and submit any supporting documentation (eg, patient discharge summary, autopsy reports.  
 Special Situation Reporting Requirements 
 Definitions of Special Situations 
Special situations include pregnancy; medication error, abuse, misuse, or overdose; and adverse 
reactions associated with product complaints: 
• Information regarding pregnancy is provided in Section 9.4.2. 


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• A medication error is any preventable event that can cause or lead to inappropriate 
medication use or patient harm while the medication is in the control of a healthcare 
professional, patient, or consumer. 
• Abuse is defined as persistent, sporadic, or intentionally excessive use of a drug by a 
patient when such use is accompanied by harmful physical and/or psychological effects. 
• Misuse is defined as any use of a drug in a way that is not in accordance with the protocol 
instructions or the local prescribing information and may be accompanied by harmful 
physical and/or psychological effects. 
• An overdose is defined as a dose taken (accidentally or intentionally) exceeding the 
overdose limit as prescribed by the protocol. In the case of a discrepancy in drug 
accountability, an overdose will be established only when it is clear that the patient has 
received an excess dose or the Investigator has reason to suspect that the patient has 
received an excess dose. 
o For this protocol, an overdose of tomivosertib is defined as a daily dose more than 
25% of the dose assigned for that patient. See Section 6.2.1 for supportive care 
guidelines in the event of overdose. 
• A product complaint is defined as any written or verbal report arising from potential 
deviations in the manufacture, packaging, or distribution of a product. 
 Partner Pregnancy 
The Investigator should report the partner pregnancy to Sponsor designee within 24 hours of 
being notified, in the same manner as for reporting SAEs (see Section 9.3). A Pregnancy Report 
Form will be supplied. Monitoring of the pregnancy in female partners of male study patients 
should continue until the conclusion of the pregnancy. For female partners of male study 
patients, such monitoring applies if the pregnancy occurs in the period from the patient’s start of 
study drug until 30 days after the patient’s last dose of study drug. The outcome of the pregnancy 
should be reported on the pregnancy outcome report form within 24 hours of the Investigator’s 
awareness of the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported to Sponsor designee (see Section 9.3). 
 Instructions for Reporting Special Situations 
Information regarding all other special situations must be documented on the special situations 
report form and forwarded to Sponsor designee within 24 hours of learning of the event. 
Along with information regarding the circumstances of the special situation, any clinical 
sequelae occurring in association with that situation should be reported as AEs or SAEs 
according to the reporting requirements for those events (see Section 9.3). Details of signs or 
symptoms, clinical management, and outcome should be reported, if available. 
9.4.3.1 All Other Special Situations 
Information regarding all other special situations must be documented on the special situations 
report form and forwarded to Sponsor designee within 24 hours of learning of the event. 


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Along with information regarding the circumstances of the special situation, any clinical 
sequelae occurring in association with that situation should be reported as AEs or SAEs 
according to the reporting requirements for those events (see Section 9.3). Details of signs or 
symptoms, clinical management, and outcome should be reported, if available. 
 Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the Food and Drug 
Administration (FDA), applicable competent authorities in all Member States concerned, and to 
the Central Ethics Committee, and in any case no later than 7 days after knowledge by the 
Sponsor of such a case, and that relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other suspected unexpected serious adverse reactions will be reported to the FDA, applicable 
competent authorities concerned, and to the Central Ethics Committee concerned as soon as 
possible but within a maximum of 15 days of first knowledge by the Sponsor.  
The Sponsor or designee will also inform all Investigators as required.  
Expedited reporting of suspected unexpected serious adverse reactions related to any 
non-investigational medical products will not be necessary. Listings of cases related to any 
non-investigational medical products will be included in the Development Safety Update Report. 


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10 STATISTICAL CONSIDERATIONS 
This section describes the statistical considerations and data analyses to address the objectives of 
the study. Further details will be provided in the Statistical Analysis Plan (SAP). A separate PK 
Analysis Plan may be generated to describe data analyses related to the PK objectives. 
 
General Considerations 
All safety, efficacy, PK, pharmacodynamic, CTC, and P-eIF4E data where available will be 
listed by patient. Baseline is defined as the last observed measurement, whether scheduled or 
unscheduled, prior to first study drug administration.  
Continuous variables will be summarized using the number of patients with data (n), mean, 
standard deviation, median, minimum, and maximum. Selected continuous variable summaries 
will also include the standard error. Categorical variables will be summarized using frequency 
counts and percentages. The 95% confidence intervals (CIs) will be calculated and reported for 
efficacy endpoints. 
All analyses, including summaries and listings, will be performed using SAS® software 
Version 9.1 or higher. 
Hypothesis testing may be performed for selected pharmacodynamic and efficacy endpoints. 
Inflation of the Type 1 error rate is a concern because this study defines two co-primary 
endpoints. There will, however, be no adjustments to control the Type I error rate for multiple 
comparisons. This study is considered exploratory in nature with the overall goal of looking for 
any anti-tumor activity. Any statistically significant findings will be considered hypothesis-
generating for future studies. 
Final study reporting is expected to occur after the last patient completes the End-of-Treatment 
Visit or the last patient completes 6 months of therapy, whichever occurs first. Addenda to the 
study report may be created (eg, to provide long-term follow-up or OS information). 
 
Analysis Populations 
Full Analysis Population: The Full Analysis Population will include all enrolled patients. This 
analysis set will be used for all disposition, demographic, and disease history summaries. 
Safety Population: The Safety Population will include all enrolled patients who receive 1 dose 
of tomivosertib. This analysis set will be used for all safety and efficacy analyses. 
Efficacy Evaluable Population: The Efficacy Evaluable Population will include all patients who 
receive 1 dose of tomivosertib and have sufficient baseline and on-study assessments to 
characterize response. This analysis set may be used in a sensitivity analysis for select efficacy 
endpoints.  
 
Determination of Sample Size 
Simon’s 2-stage design will be used to evaluate the tumor response rate. The null hypothesis that 
the true response rate is 5% will be tested against a one-sided alternative. In the first stage, 
13 patients will be accrued. If there are no responses in these 13 patients after a minimum of 
16 weeks of exposure to tomivosertib, the study will be stopped. Otherwise, 14 additional 


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evaluable patients will be accrued for a total of 27 patients. The null hypothesis will be rejected 
if 4 or more responses are observed in 27 patients.  
Enrollment of approximately 30 patients is planned to have 27 evaluable patients to target a 
tumor response rate of ≥20%. 
 
Analysis Methods 
 Disposition, Demographics, and Disease History 
Patient disposition, demographics, and baseline disease and treatment characteristics will be 
summarized for the Full Analysis Population. Summaries of patient disposition will include the 
number of patients enrolled, treated with tomivosertib, and discontinuing treatment with reason 
for study withdrawal. A summary of analysis sets will also be provided. 
Patient demographics and disease history will be listed and summarized. Separate summaries of 
demographics may be produced for the Safety Population if warranted. Medical history will be 
summarized and presented in a listing. 
 Study Drug Exposure and Compliance 
The Safety Population will be used for summaries of study drug exposure and compliance. 
Descriptive information will be provided regarding the number of cycles of therapy 
administered, the number (%) of completed cycles, the number (%) of cycles delayed, the 
number of doses of study drug taken, the number of days of treatment, the number of dose 
modifications and interruptions, and the reasons for dose modifications and interruptions. 
The cumulative number of days of dosing and cumulative dose in mg will be summarized. 
Study drug compliance will be described in terms of the number (%) of days study drug was 
reported taken relative to the number of days study drug was expected to be taken over a 
specified period of time. 
 Prior and Concomitant Medications 
The Safety Population will be used for summaries of prior and concomitant medications. 
Prior, concomitant, and postdose medications will be coded by means of the World Health 
Organization Drug Dictionary (WHODRUG) into Anatomical Therapeutic-Chemical (ATC) 
classification codes. Descriptions of prior medication use will be focused on drugs and regimens 
used as treatments for cancer. As appropriate and if available, information on the sequencing, 
type, dose, schedule, timing, duration of use, and efficacy of prior regimens will be provided. 
Descriptions of prior medications used during the screening period will also be provided. 
The use of concomitant medications and supportive care will be listed and summarized. 
Information regarding the type and amounts of specific supportive medications or measures (eg, 
antidiarrheals, antiemetics, antipyretics, anti-inflammatories, corticosteroids) will be described. 
Poststudy treatment regimens for cancer will be listed. 


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 Safety Analyses 
The Safety Population will be used for all safety analyses and listings. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AEs that 
start during or after initiating study drug or that worsen after study drug initiation will be 
considered treatment-emergent adverse events (TEAEs). TEAEs will be coded and tabulated by 
System Organ Class and Preferred Term. Incidence of TEAEs and SAEs will be summarized and 
results will be presented in descending order of frequency. TEAEs will also be summarized by 
severity and according to their relationship to study drug. TEAE summaries will be generated for 
the entire study period as well as by treatment cycle. 
Selected clinical safety laboratory parameters will be presented in summary tables. Changes 
from baseline in laboratory parameters, ECOG performance status, ECG parameters, and vital 
signs will be summarized. Selected laboratory parameters will be summarized in shift tables by 
CTCAE grade. For laboratory tests without CTCAE grade definitions, results will be categorized 
as normal, abnormal, or not done. 
 Efficacy Analyses 
The Safety Population will be used for all efficacy analyses and listings. Additional analyses 
may be performed on other analysis populations including the Efficacy Evaluable Population. 
Efficacy will be evaluated using PSA levels, tumor response according to iRECIST criteria, and 
bone scan results. Tumor control will be documented at each assessment by PSA percent change 
from baseline and by iRECIST response category (eg, iCR, iPR, stable disease [iSD], 
unconfirmed progressive disease [iUPD], iCPD, or nonevaluable [NE]). iRECIST objective 
response includes response categories of iCR and iPR. Progression will also be monitored using 
PCWG2 PSA and bone progression criteria. PSA levels, iRECIST tumor assessments, and bone 
scan results will be presented in patient data listings that include, but are not limited to, tumor 
type, tomivosertib dose, sum of tumor diameters, tumor response at each disease assessment, and 
best overall response. In addition, date of first response for PSA and iRECIST, date of 
confirmation of response, date of PSA, bone, iRECIST disease progression, date of last tumor 
assessment, date of death, and date of last contact will be listed. 
10.4.5.1 Definition of Efficacy Endpoints 
Anti-tumor response will be defined on the basis of the following co-primary endpoints. A 
patient will be considered a responder if he achieves either of the following outcomes: 
• A ≥50% PSA decline from baseline at any time point after therapy and maintained for 
≥4 weeks 
• Objective response according to iRECIST 
Secondary efficacy time-to-event endpoints include: 
• PSA progression-free survival (PCWG2 criteria [Scher 2008]) defined as the interval 
from the start of study therapy until the date PSA progression is first observed. PSA 
progression is defined as a ≥25% increase in PSA from nadir or baseline (and by 
≥2 ng/mL) and requires confirmation ≥3 weeks later. 


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• Clinical and radiological progression-free survival (iPFS by iRECIST) defined as the 
interval from the start of study therapy until the first date at which progression criteria are 
first met (the date of iUPD), provided that iCPD is confirmed at the next assessment, or 
death from any cause (whichever occurs first). If iUPD occurs but is disregarded because 
of later iSD, iPR, or iCR, that iUPD date should not be used as the progression event 
date. If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, then 
the iUPD date should still be used in the following scenarios: if the patient stops protocol 
treatment because he was not judged to be clinically stable, or no further response 
assessments are done (because of patient refusal, protocol non-compliance, or patient 
death); the next timepoint responses are all iUPD and iCPD never occurs; or the patient 
dies from his cancer. 
• 
PCWG2 bone progression-free survival defined as the interval from the start of study 
therapy until bone progression. Bone progression is defined as the presence of 2 or more 
new bone lesions as well as a confirmatory scan performed 6 or more weeks later that 
shows additional new lesions. When progression is documented on the confirmatory 
scan, the date of bone progression is the date of the first scan showing 2 or more new 
bone lesions.  
• Overall Survival (OS) defined as the interval from the start of study therapy to death from 
any cause. 
10.4.5.2 Analysis of Efficacy Endpoints 
The PSA response rate and iRECIST response rate will be summarized. The number and percent 
of patients who are PSA responders and responders according to iRECIST criteria will be 
presented along with 95% confidence intervals for the proportions. Patients who do not have 
sufficient baseline and on-study tumor assessments to characterize response (ie, have a best 
overall response of NE or no post-baseline PSA assessments) will be counted as failures.  
The number and percent of patients meeting PCWG2 bone and PSA progression criteria will also 
be summarized along with 95% confidence intervals for the proportions.  
Time-to-event endpoints will be summarized using Kaplan-Meier methods. Medians and ranges 
will be presented as well as 95% confidence intervals for the median survival time. Censoring 
methods for all time-to-event endpoints will be described in the SAP. 
 Pharmacokinetic Analyses 
Plasma concentrations of tomivosertib will be determined using validated liquid chromatography 
tandem-mass spectrometry assays. Plasma concentrations of tomivosertib will be summarized by 
scheduled time point with descriptive statistics, which will include the n, mean, standard 
deviation, coefficient of variation (%), median, minimum, and maximum. PK data may be 
analyzed by model-based PK analyses. Population PK analysis may be analyzed separately. 
 Exploratory Analyses 
Tumor tissue samples (archival or fresh) when submitted will be examined for P-eIF4E. An 
immunoscore ranging from 0 to 300 will be determined for each sample. Blood samples will be 
assessed for CTC count and AR-V7 expression. The relationship(s) between P-eIF4E 


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immunoscore, CTC count, AR-V7 expression, and efficacy endpoints for disease will be 
examined using statistical methods including, but not limited to, analysis of variance.  
 Interim Analysis 
The study design utilizes a Simon 2-stage minimax approach to evaluate the anti-tumor activity. 
In the first stage, 13 patients will be accrued. If there are no responses in these 13 patients after a 
minimum of 16 weeks of exposure to tomivosertib, the study will be stopped.  
No formal interim analysis is planned. Safety data from all patients will be monitored on an 
ongoing basis. 


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11 STUDY ADMINISTRATION AND RESPONSIBILITIES 
 General Investigator Responsibilities 
The Principal Investigator must ensure that: 
• He or she will personally conduct or supervise the study. 
• His or her staff and all persons who assist in the conduct of the study clearly understand 
their responsibilities and have their names included in the Study Personnel 
Responsibility/Signature Log. 
• The study is conducted according to the protocol and all applicable regulations. 
• The protection of each patient’s rights and welfare is maintained. 
• Signed and dated informed consent and, when applicable, permission to use protected 
health information are obtained from each patient before conducting study procedures. If 
a patient withdraws permission to use protected health information, the Investigator will 
obtain a written request from the patient and will ensure that no further data be collected 
from the patient. 
• The consent process is conducted in compliance with all applicable regulations and 
privacy acts. 
• The IRB complies with applicable regulations and conducts initial and ongoing reviews 
and approvals of the study. 
• Any amendment to the protocol is submitted promptly to the IRB. 
• Any significant protocol deviations are reported to the Sponsor and their study 
representatives, and the IRB according to the guidelines at each study site. 
• eCRF pages are completed within 5 days of each patient’s visit (unless required earlier 
for SAE reporting). 
• All SAEs are reported to the Sponsor or designee within 24 hours of knowledge and to 
the IRB per IRB requirements. 
• All safety reports are submitted promptly to the IRB. 
 Protocol Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
 Protocol Deviations 
A protocol deviation occurs when the patient or investigator fails to adhere to 
inclusion/exclusion criteria, conduct of the trial, patient management or patient assessment that 
impact the safety of the patients or jeopardize the quality of the study data. Protocol deviations 
for this study include, but are not limited to, the following: 
• Failure to meet inclusion/exclusion criteria 


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• Withdrawal criteria met but patient not withdrawn 
• Wrong treatment or incorrect dose that are not within the protocol specifications 
• Use of a prohibited concomitant medication 
• Any other deviation that presents significant risk or safety concerns to the patient 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
deviation. The Sponsor, in consultation with the investigator, will determine if a protocol 
deviation should result in withdrawal of a patient. 
 Compliance with Ethical and Regulatory Guidelines 
The Investigator will ensure that this study is conducted in accordance with International Council 
for Harmonisation (ICH) guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study patient. For studies 
conducted under a United States Investigational New Drug (IND) application, the Investigator 
will ensure adherence to the basic principles of GCP as outlined in 21 Code of Federal 
Regulations (CFR) 312, subpart D, “Responsibilities of Sponsors and Investigators”; 21 CFR, 
Part 50, 1998; and 21 CFR, Part 56, 1998. 
This study is also patient to and will be conducted in accordance with 21 CFR, Part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.” 
Because this is a “covered” clinical study, the Investigator will ensure adherence to 21 CFR, 
Part 54, 1998; a covered clinical study is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition patient to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that Investigators and all sub-Investigators must provide documentation of their 
financial interest or arrangements with the Sponsor, or proprietary interests in the drug being 
studied. This documentation must be provided before participation of the Investigator and any 
sub-Investigator in the study. The Investigator or sub-Investigator agrees to notify the Sponsor of 
any change in reportable financial interests during the study and for 1 year following completion 
of the study. Study completion is defined as the date that the last patient has completed the 
protocol-defined activities. 
 Institutional Review Board 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the Investigator to an IRB. Approval from the IRB must be 
obtained before starting the study and should be documented in a letter from the IRB to the 
Investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. A signed protocol 
approval page, a letter confirming IRB approval of the protocol and informed consent, and a 
statement that the IRB is organized and operates according to GCP and the applicable laws and 
regulations must be forwarded to the Sponsor before screening patients for the study. 
Additionally, study sites must forward a signed Form FDA 1572 (Investigator Obligation Form) 
to the Sponsor before screening patients for study enrollment. 


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Any modifications or amendments made to the protocol or informed consent document after 
receipt of the initial IRB approval must also be submitted to the IRB for approval before 
implementation. Only changes necessary to eliminate apparent immediate hazards to the patients 
may be initiated prior to IRB approval. In that event, the Investigator must notify the IRB and the 
Sponsor or their designee in writing within 5 working days after implementation. If a change to 
the protocol in any way increases the risk to the patient or changes the scope of the study, then 
written documentation of IRB approval must be received by the Sponsor before the amendment 
may take effect. Additionally, under this circumstance, information on the increased risk and/or 
change in scope must be provided to patients already actively participating in the study, and they 
must read, understand, and sign any revised informed consent document confirming willingness 
to remain in the study. 
The Investigator shall submit a progress report at least once yearly to the IRB and must provide a 
copy to the Sponsor. As soon as possible after completion or termination of the study, the 
Investigator will submit a final report to the IRB and to the Sponsor. This report should include 
the dates of initiation and completion of the study, a description of any changes in study 
procedures or amendments to the protocol, any deviations from the protocol, the number and 
type of patients evaluated, the number of patients who discontinued (and the reasons for 
discontinuation), the number of patients who completed the study, and the results of the study, 
including a description of any AEs. The Sponsor will assist the Investigator in the preparation of 
this report, as needed. 
 Informed Consent Process 
Note: All references to “patient” in this section refer to the study patient or his/her legally 
authorized representative. 
The Sponsor (or its designee) will provide Investigators with a multicenter Informed Consent 
Document(s) for this study. Investigators may adapt the information to suit the needs of their 
institution, if necessary (although it must reflect the required elements of informed consent 
specified in 21 CFR Part 50.25). The final Informed Consent Document(s) must be accepted by 
the Sponsor and approved by the IRB. Investigators must provide the Sponsor with an unsigned 
copy of the final Informed Consent Document(s) before and after it is approved by the IRB. If 
any new information becomes available that might affect patients’ willingness to participate in 
the study, or if any amendments to the protocol require changes to the Informed Consent 
Document(s), the Sponsor will provide Investigators with an Informed Consent Document(s). 
Prior to participating in any study-related procedure, each patient must sign and date an 
IRB-approved Informed Consent Document(s) written in a language the patient can understand. 
The Informed Consent Document(s) should be as nontechnical as practical and understandable to 
the patient. The Informed Consent Document(s) must provide the patient with all the information 
necessary to make an informed decision about their participation in the study, including the 
nature and intended purpose of the study, possible benefits, possible risks, and disclosures of the 
patient’s personal information and personal health information for purposes of conducting the 
study. The Informed Consent Document(s) will include details of the requirements of the 
participant and the fact that he/she is free to withdraw at any time without giving a reason and 
without prejudice to his/her further medical care. Before informed consent is obtained, the 
patient should be given ample time and opportunity to inquire about the details of the study. All 
questions must be answered to the satisfaction of the patient. 


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Once signed, the original Informed Consent Document(s) will be stored in the Investigator’s site 
file and made available for review by the Sponsor. Documentation of the informed consent 
discussion must be noted in the patient’s case history. All patients will receive a copy of their 
signed and dated Informed Consent Document(s). 
If the Informed Consent Document(s) is revised during the study and requires the patient to be 
re-consented, informed consent will be obtained in the same manner as for the original Informed 
Consent Document(s). 
 Confidentiality 
Every effort will be made to maintain the anonymity and confidentiality of all patients during 
this clinical study. However, because of the experimental nature of this study drug, the 
Investigator agrees to allow the IRB, representatives of the Sponsor and its designated agents, 
and authorized employees of appropriate regulatory agencies to inspect the facilities used in this 
study and, for purposes of verification, allow direct access to the study site records of all patients 
enrolled into this study. This includes providing by fax, e-mail, or regular mail de-identified 
copies of clinical, laboratory, ECG, radiology, pathology, and/or other test results when 
requested by the Sponsor. A statement to this effect will be included in the Informed Consent 
Document(s) and a permission form authorizing the use of protected health information will also 
be included. 
In accordance with local and national patient privacy regulations, the Investigator or designee 
must explain to each patient that in order to evaluate study results, the patient’s protected health 
information obtained during the study may be shared with IRBs, the Sponsor and its designees, 
and regulatory agencies. It is the Investigator’s or designee’s responsibility to obtain written 
permission to use protected health information from each patient. If a patient withdraws 
permission to use protected health information, it is the Investigator’s responsibility to obtain the 
withdrawal request in writing from the patient and to ensure that no further data will be collected 
from the patient. Any data collected on the patient before withdrawal will be used in the analysis 
of study results. The Sponsor will only use or disclose the patient’s protected health information 
consistent as defined in the Informed Consent Document(s). 
The Investigator must assure that each patient’s anonymity will be strictly maintained and that 
each patient’s identity is protected from unauthorized parties. Only patient initials, date of birth, 
and an identification code (but no patient names) should be recorded on any form or biological 
sample submitted to the IRB, to the Sponsor or its designees (eg, laboratories), or to regulatory 
authorities. However, sufficient information must be retained at the study site to permit sample 
data and data in the database to be connected with the unique patient number assigned to each 
study participant. 
The Investigator agrees that all information received from the Sponsor, including, but not limited 
to, the study drug, the IB, this protocol, the eCRFs, and any other study information remain the 
sole and exclusive property of the Sponsor during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
Sponsor. The Investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 


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 Study Files and Retention of Records and Biological Samples 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified by the IRB, representatives 
of the Sponsor and its designated agents, and authorized employees of appropriate regulatory 
agencies. These documents should be classified into at least the following 2 categories: 
(1) Investigator’s study file, and (2) patient clinical source documents. 
The Investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB and governmental approval with correspondence, signed Informed Consent Documents, 
drug accountability records, staff curriculum vitae and authorization forms (eg, Form 
FDA 1572), and other appropriate documents and correspondence pertaining to the conduct of 
the study. 
The required source data referenced in the monitoring plan for the study should include 
sequential notes containing at least the following information for each patient: 
• Patient identification (name, date of birth, sex). 
• Documentation that patient meets eligibility criteria, eg, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria). 
• Participation in study (including study number). 
• Study discussed and date of informed consent. 
• Dates of all visits. 
• Documentation that protocol-specific procedures were performed. 
• Results of efficacy parameters, as required by the protocol. 
• Start and end date (including dose regimen) of study drug (including relevant drug 
dispensing information). 
• Record of all AEs and other safety parameters (including start and end date, causality, 
and intensity). 
• Concomitant medications (including start and end date and dose if relevant dose changes 
occur). 
• Date of study completion and reason for discontinuation, if applicable. 
All clinical study documents must be retained by the Investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and regulatory authorities have been notified or for 
15 years, whichever is longer. Investigators may be required to retain documents longer if 
required by applicable regulatory requirements, by local regulations, or by an agreement with the 
Sponsor. The Investigator must notify the Sponsor and obtain written approval from the Sponsor 
before destroying any clinical study records. The Investigator will promptly notify the Sponsor in 
the event of accidental loss or destruction of any study records. The Sponsor will inform the 
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The Sponsor must be notified in advance and must provide express written approval of any 
change in the maintenance of the foregoing documents if the Investigator wishes to move study 
records to another location or assign responsibility for record retention to another party.  
If the Investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor to 
store these in sealed containers outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the study site. 
Biological samples retained by the Investigator will be stored and maintained by the Investigator 
until notification is received from the Sponsor that the retained samples and records no longer 
need to be retained. The Investigator must obtain written permission from the Sponsor before 
disposing of any retained samples. The Investigator should promptly notify the Sponsor in the 
event of accidental loss or destruction of any study samples. With the permission of the Sponsor, 
the retained samples may be transferred to an acceptable designee, such as another Investigator, 
another institution, a contract storage site, or to the Sponsor. 
 Patient Screening Log 
The Investigator will be asked to keep a record that lists all patients who signed the Informed 
Consent Document (including those who did not undergo screening). For those patients who 
declined to participate or were subsequently excluded from enrollment, the reasons for not 
enrolling in the study must be described. 
 Modifications of the Protocol or Informed Consent Documents 
Protocol modifications, except those intended to reduce immediate risk to study patients, will be 
made only by the Sponsor. All protocol modifications must be submitted to the IRB in 
accordance with local requirements. Except as noted in Section 11.4, IRB approval must be 
obtained before changes can be implemented. 
Informed Consent Document(s) cannot be changed without prior approval by the Sponsor and 
the study site’s IRB. 
 Case Report Forms 
Authorized study site personnel will complete eCRFs designed for this study according to the 
completion guidelines that will be provided. An eCRF is required and must be completed for 
each enrolled patient, with all required study data accurately recorded such that the information 
matches the data contained in medical records (eg, physicians’ notes, nurses’ notes, study site 
charts, or other study-specific source documents). The Investigator will ensure that the eCRFs 
are accurate, complete, and legible. The Investigator will ensure that source documents that are 
required to verify the validity and completeness of data transcribed on the eCRFs are never 
obliterated or destroyed. As required by the protocol, eCRFs should also be completed for those 
patients who fail to complete the study (even during the screening period). If a patient withdraws 
from the study, the reason must be noted on the eCRF and thorough efforts should be made to 
clearly document outcome. 


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The eCRFs for this study will exist within a web-based electronic data capture (EDC) system. 
After the Investigator or the Investigator’s designees (eg, research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the EDC 
system, with all changes tracked by the system to provide an audit trail. 
The eCRF must be completed and signed by the principal Investigator or sub-Investigator (as 
appropriate) within a reasonable time period after data collection. This signature serves to attest 
that the information contained in the eCRF is true. 
 Clinical Monitoring 
Representatives of the Sponsor or its designee will monitor this study until completion. 
Monitoring will be conducted through personal visits with the Investigator and study site staff as 
well as any appropriate communications by mail, fax, e-mail, or telephone. The monitor is 
responsible for routine review of the eCRFs at regular intervals throughout the study to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered on them. The purpose of monitoring is to ensure compliance with the protocol and the 
quality and integrity of the data. 
In accordance with GCP, the study monitor must have direct access to the Investigator’s source 
documentation in order to verify the data recorded in the eCRFs for consistency. The 
Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are resolved. 
 Inspections 
The source documents for this study must be made available to appropriately qualified personnel 
from the Sponsor or its representatives, to the IRB, and to regulatory authority or health authority 
inspectors as a part of their responsibility to protect human patients in research. The Investigator 
agrees to provide access to records, facilities, and personnel for the effective conduct of any 
inspection or audit to representatives of the Sponsor and regulatory agencies. It is important that 
the Investigator and relevant institutional personnel are available during monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process. If the Investigator 
is notified of an inspection by a regulatory authority, the Investigator agrees to notify the 
Sponsor immediately. 
 Data Management 
EDC will be used to enter study data eCRFs and to transfer the data into a study-specific 
electronic database. During the data collection process, automated quality assurance programs 
will be used to identify missing data, out-of-range data, and other data inconsistencies. Requests 
for data clarification or correction will be forwarded to the investigative study site for resolution. 
As appropriate, eCRFs, listings, tables, and SAS datasets will be provided to the study sites for 
review. 
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide an audit trail, security mechanisms, and electronic 


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signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures. 
Data security will be controlled through appropriate and specific restriction of access to only data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study sites and at the 
Sponsor or its designee. The database will exist on physically secured servers. Data backups will 
be done regularly and will be stored in separate facilities. Printed documents relating to the study 
will be secured when not under review.  
 Clinical Study Insurance 
The Sponsor will secure clinical study insurance. An insurance certificate will be made available 
to the participating study sites before study initiation. 
 Communications with Regulatory Authorities 
The Sponsor, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. The Sponsor will maintain an IND 
for the study drug in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities as required for conduct of the study. In 
fulfilling this responsibility, the Sponsor (or a designee) will collect, assemble, and communicate 
all required regulatory documents (eg, Form FDA 1572, Investigator financial disclosure forms, 
protocol and protocol amendments, IB, informed consent documents, annual reports) as required 
by regulation. The Sponsor (or a designee) will also assume responsibility for AE reporting to 
regulatory authorities as described in Section 9.5. 
 Publication and Information Disclosure Policy 
All information provided by the Sponsor and all data and information generated by the site as 
part of the study (other than a patient’s medical records) are the sole property of the Sponsor. 
For clinical interventional studies in patients, eFFECTOR will post study results on websites 
such as https://clinicaltrials.gov/ in accordance with FDA reporting rules.  
Any publication or presentation of the results of this study may only be made in compliance with 
the provisions outlined in the executed Clinical Trial Agreement. Publication of scientific and 
clinical data will follow the recommendations of the International Committee of Medical Journal 
Editors, the Consolidated Standards of Reporting Trials group, and Good Publication Practice. 
 Study Discontinuation 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures. The Investigator will be 
responsible for notifying the relevant study site’s IRB. The Sponsor will be responsible for 
notifying the appropriate regulatory authorities. In terminating the study, the Sponsor and the 
Investigator will assure that adequate consideration is given to the protection of the patients’ 
interests. As directed by the Sponsor, all study materials must be collected and all eCRFs 
completed to the greatest extent possible. 


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Res. 2004 Dec 1;64(23):8639-8642. 
Truitt ML, Conn CS, Shi Z, et al. Differential requirements for eIF4E dose in normal 
development and cancer. Cell. 2015 Jul 2;162(1):59-71. 
Ueda T, Watanabe-Fukunaga R, Fukuyama H, Nagata S, Fukunaga R. MNK2 and MNK1 are 
essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not 
for cell growth or development. Mol Cell Biol. 2004 Aug;24(15):6539-6549. 


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Vale CL, Burdett S, Rydzewska LHM, et al. Addition of docetaxel or bisphosphonates to 
standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a 
systematic review and meta-analyses of aggregate data. Lancet Oncol. 2016;17:243-256. 
Wang X, Flynn A, Waskiewicz AJ, et al. The phosphorylation of eukaryotic initiation factor 
eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP 
kinase pathways. J Biol Chem. 1998 Apr 17;273(16):9373-9377. 
Waskiewicz AJ, Flynn A, Proud CG, et al. Mitogen-activated protein kinases activate the 
serine/threonine kinases MNK1 and MNK2. EMBO J. 1997 Apr 15;16(8):1909-1920. 
Wendel HG, Silva RL, Malina A, et al. Dissecting eIF4E action in tumorigenesis. Genes Dev. 
2007 Dec 15;21(24):3232-3237. 
Wu JN, Fish KM, Evans CP, et al. No improvement noted in overall or cause-specific survival 
for men presenting with metastatic prostate cancer over a 20-year period. Cancer. 2014;120:818-
823. 
Zhou CK, Check DP, Lortet-Tieulent J, et al. Prostate cancer incidence in 43 populations 
worldwide: an analysis of time trends overall and by age group. Int J Cancer. 2016;138:1388–
1400. 
 


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13 APPENDICES 
 
 


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 Sponsor Protocol Approval 
Protocol Title: 
A Phase 2 Non-randomized Open-label Study Examining the 
Effect of eFT508 in Patients with Advanced Castrate-resistant 
Prostate Cancer (CRPC) 
Protocol Number: 
eFT508-0009 
Protocol Version (Date): 
Version 3.0 – 30 November 2018 
 
This version of the clinical protocol has been approved by eFFECTOR Therapeutics, Inc. 
 
 
 
 
Title: Jeremy Barton, CMO 
eFFECTOR Therapeutics, Inc. 
 
Date 
 
 
 


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 Principal Investigator Agreement 
Protocol Title: 
A Phase 2 Non-randomized Open-label Study Examining the 
Effect of eFT508 in Patients with Advanced Castrate-resistant 
Prostate Cancer (CRPC) 
Protocol Number: 
eFT508-0009 
Protocol Version (Date): 
Version 3.0 – 30 November 2018 
 
I have reviewed this version of the protocol and – on behalf of my institution – agree to 
conduct the study as outlined herein and in compliance with Good Clinical Practice and all 
applicable regulatory requirements. I understand that neither I nor any member of my staff 
may modify this protocol without obtaining written concurrence of eFFECTOR Therapeutics, 
Inc. (eFFECTOR), and that eFFECTOR and the Institutional Review Board must approve any 
substantive changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after termination of the study, any 
confidential information acquired regarding the investigational product and eFFECTOR 
processes or methods. All data pertaining to this study will be provided to eFFECTOR. I 
understand that any presentation or publication of study data must be generated by 
eFFECTOR, as specified in the protocol. 
I certify that neither I nor any member of my staff have been disqualified or debarred by the 
United States Food and Drug Administration or any European regulatory body for clinical 
investigations or any other purpose. 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
Printed Name 
 
 
 
 


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 Eastern Cooperative Oncology Group Performance Status Scale 
Table 4: Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
Reference: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982 Dec;5(6):649-655. 
 
 


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 Cockcroft-Gault Method for Estimating Creatinine Clearance 
Formulas for calculating the estimated creatinine clearance are provided below. The formula 
appropriate to the units in which serum creatinine was measured and the patient’s sex should be 
used. 
Table 5: Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance 
Serum  
Creatinine Units 
Sex 
Formula 
 
 
 
 
 
 
mg/dL 
Males 
eClCR 
[mL/min] = (140-patient age [years])  patient weight [kilograms]  1.0 
72  patient serum creatinine [mg/dL] 
 
 
 
 
Females 
eClCR 
[mL/min] = (140-patient age [years])  patient weight [kilograms]  0.85 
72  patient serum creatinine [mg/dL] 
 
 
 
 
 
 
µM/dL 
Males 
eClCR 
[mL/min] = (140-patient age [years])  patient weight [kilograms]  1.23 
Patient serum creatinine [µM/dL] 
 
 
 
 
Females 
eClCR 
[mL/min] = (140-patient age [years])  patient weight [kilograms]  1.04 
Patient serum creatinine [µM/dL] 
 
 
 
 
 
Abbreviations: eClCR, estimated creatinine clearance. 
 
 


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 Strong Inhibitors and Inducers of Cytochrome P450 (CYP)3A4 
Table 6: Strong Inhibitors and Inducers of Cytochrome P450 (CYP)3A4 
Effect on 
CYP3A  
Drug Class 
Medications 
Strong CYP3A 
Inhibitors 
Antibiotics 
clarithromycin, troleandomycin 
Antifungals 
ketoconazole, itraconazole, posaconazole, voriconazole 
Antiviral 
protease inhibitors 
danoprevir and ritonavir, elvitegravir and ritonavir, indinavir 
and ritonavir, lopinavir and ritonavir, nelfinavir, paritaprevir 
and ritonavir and (ombitasvir and/or dasabuvir), ritonavir, 
saquinavir and ritonavir, telaprevir, tipranavir, and ritonavir 
Calcium-channel blockers 
diltiazem 
Foods/herbs 
grapefruit juice 
Pharmacokinetic enhancer 
cobicistat 
Phosphatidylinositol 
3-kinase inhibitor 
idelalisib 
Serotonin antagonist 
nefazodone 
Vasopressin antagonist 
conivaptan 
Strong CYP3A 
Inducers 
 
Androgen receptor inhibitor 
enzalutamide 
Antibiotics 
rifampin 
Anticonvulsants 
carbamazepine, phenytoin 
Antineoplastic agent 
mitotane 
Foods/herbs 
St. John’s wort 
Abbreviations: CYP, cytochrome P450. 
Reference: Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers. 9/26/2016. Available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm 
(accessed 04 January 2017). 
 
 


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Immune-Related Response Evaluation Criteria in Solid Tumors 
All patients will have their tumor response assessed using Response Evaluation Criteria in Solid 
Tumors (iRECIST) guidelines. iRECIST is based on RECIST 1.1, therefore RECIST 1.1 
guidelines will be used for the identification, method of measurement, and management of 
lesions. 
 Definitions of Disease  
13.6.1.1 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in 1 dimension 
(longest diameter to be recorded) as >10 mm with CT scan (with minimum slice thickness of 
5 mm), or >10 mm caliper measurement by clinical exam, or >20 mm by chest X-ray. 
Pathological lymph nodes may also be considered as target or nontarget lesions. To be 
considered pathologically enlarged and measurable (target lesion), a lymph node must be 
15 mm in short axis when assessed by CT scan (minimum slice thickness of 5 mm). Lymph 
nodes with a short axis 10 mm but <15 mm should be considered nontarget lesions. Lymph 
nodes that have a short axis <10 mm are considered nonpathologic and should not be recorded as 
target lesions at baseline. 
13.6.1.2 Nonmeasurable Disease 
Nonmeasurable disease comprises all other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with 10 to <15 mm short axis) as well 
leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory breast disease, 
lymphangitis cutis or pulmonis, abdominal masses, or organomegaly identiﬁed by physical exam 
that is not measurable by reproducible imaging techniques. 
13.6.1.3 Other Disease 
Bone lesions: Bone scan, PET scan or plain ﬁlms are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to conﬁrm the 
presence or disappearance of bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with 
identiﬁable soft tissue components, that can be evaluated by cross-sectional imaging techniques 
such as CT or MRI can be considered as measurable lesions if the soft-tissue component meets 
the deﬁnition of measurability described in Section 13.6.1.1. Blastic bone lesions are considered 
nonmeasurable. 
Cystic lesions that meet the criteria for radiographically deﬁned simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
deﬁnition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the deﬁnition of measurability described in Section 13.6.1.1. 
However, if non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Tumor lesions situated in a previously irradiated area, or in an area patiented to other 
locoregional therapy, are not considered measurable unless there has been demonstrated 


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progression in the lesion. Such lesions should not be selected as target lesion when other 
measurable lesions are available  
 Definitions of Target and Nontarget Lesions  
13.6.2.1 Target Lesions 
Up to a maximum of 5 measurable lesions total (and a maximum of 2 lesions per organ) 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate and reproducible repeated measurements 
(either by imaging techniques or clinically).  
13.6.2.2 Nontarget Lesions 
All other lesions (or sites of disease) should be identified as nontarget lesions and should also be 
recorded at baseline. Measurements are not required and these lesions should be followed as 
“present,” “absent,” or in rare cases “unequivocal progression” (see Eisenhauer 2009 for further 
discussion of “unequivocal progression”). Nontarget lesions include measurable lesions that 
exceed the maximum number per organ or total of all involved organs as well as nonmeasurable 
lesions. It is possible to record multiple nontarget lesions involving the same organ as a single 
item on the case record form (eg, “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”). Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.  
 Guidelines for Evaluation of Disease 
13.6.3.1 Methods of Assessment 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. MRI is also acceptable in certain situations (eg, for body scans). The 
minimum slice thickness should be 5 mm. If slice thickness is >5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. 
Clinical lesions will only be considered measurable when they are superficial (eg, skin nodules 
and palpable lymph nodes). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray may be used to follow measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT of lesions is the chest is preferred. 
When available, functional fluorodeoxyglucose (FDG)-PET data can be used to complement CT 
data when assessing progressive disease but is not a formal component of disease assessment in 
this study.  
Ultrasound should not be used as a method of measurement.  
The use of endoscopy or laparoscopy for objective tumor evaluation is not advised. However, 
these techniques can be useful to conﬁrm complete pathological response when biopsies are 
obtained or to determine disease relapse. 


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Cytology or histology can be used to differentiate between PR and CR in rare cases (eg, residual 
lesions in tumor types, such as germ-cell tumors, where known residual benign tumors can 
remain). Because an effusion may be a side effect of some treatments, the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment is 
mandatory to differentiate between CR, PR, stable disease (SD), and PD. 
13.6.3.2 Reproducibility of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Ideally, the same individual 
should consistently perform assessments.  
Imaging-based evaluation is preferred to evaluation by clinical examination when both methods 
have been used to assess the antitumor effect of a treatment. To ensure comparability, the 
baseline radiology/scans and subsequent radiology/scans to assess response should be performed 
using identical techniques whenever possible (eg, scans performed immediately following bolus 
contrast administration should be made with a standard volume of contrast, the identical contrast 
agent, and the same scanner).  
13.6.3.3 Determination of Tumor Response and Progression 
All baseline evaluations should be performed as closely as possible to the beginning of treatment 
within the protocol-defined screening period.  
All sites of disease will be followed as either target or nontarget lesions, as categorized at 
baseline. All measurable lesions up to a maximum of 2 lesions per organ or 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, while all other lesions 
(either additional measurable lesions or nonmeasurable lesions) will be classified as nontarget 
lesions.  
All measurements will be taken and recorded in metric notation using a ruler or calipers. A sum 
of the diameters for all target lesions will be calculated and reported as the baseline sum of the 
diameters. For solid tumor lesions, only the long axis is added to the sum and for lymph nodes, 
only the short axis is added to the sum.  
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (eg, 2 mm). If the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If a target lesion (nodal or non-
nodal) becomes so faint on radiographic imaging that an exact measurement cannot be assigned, 
then a default value of 5 mm (minimum slice thickness) should be assigned.  
The short axis measurement of any lymph node that is considered a target lesion should continue 
to be recorded even if the node regresses to <10 mm. However, because this may prevent the 
sum of lesions from being zero even if CR criteria are met, target lymph nodes that regress to 
<10 mm can be considered to have become normal for purposes of CR calculation.  
At each post-baseline tumor assessment, the sum of the diameters of the index lesions (as defined 
in Section 13.6.1.1) (up to a maximum of 5 measurable new lesions total [2 new lesions per 
organ]) representative of all involved organs, will be added together to provide the total tumor 
burden (ie, the tumor burden=sum of the dimensions of index lesions + the sum of the 
dimensions of the selected new, measurable lesions). Comparison of the post-baseline tumor 


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burden with the baseline sum of the diameters will be used to characterize any objective tumor 
regression in the measurable dimensions of the disease. Comparison of subsequent assessments 
to the smallest sum of the diameters (nadir tumor burden), including the baseline sum if that is 
the smallest sum of the diameters during the study, will be used to characterize objective tumor 
progression in the measurable dimensions of the disease. 
 iRECIST 
The principles used to establish objective tumor response are largely unchanged from 
RECIST 1.1, but the major change for iRECIST is the concept of resetting the bar if RECIST 1.1 
progression is followed at the next assessment by tumor shrinkage. iRECIST define iUPD on the 
basis of RECIST 1.1 principles; however, iUPD requires confirmation, which is done on the 
basis of observing either a further increase in size (or in the number of new lesions) in the lesion 
category in which progression was first identified in (ie, target or non-target disease), or 
progression (defined by RECIST 1.1) in lesion categories that had not previously met 
RECIST 1.1 progression criteria. However, if progression is not confirmed, but instead tumor 
shrinkage occurs (compared with baseline), which meets the criteria of iCR, iPR, or iSD, then 
the bar is reset so that iUPD needs to occur again (compared with nadir values) and then be 
confirmed (by further growth) at the next assessment for iCPD to be assigned. If no change in 
tumor size or extent from iUPD occurs, then the timepoint response would again be iUPD. This 
approach allows atypical responses, such as delayed responses that occur after 
pseudoprogression, to be identified, further understood, and better characterized. 
 
 


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Table 4: iRECIST New Progression Confirmation 
Rules  
Worsening in Lesion Category 
iUPD TL 
≥20% SoD 
+ 
≥5 mm SoD   
= 
iCPD 
iUPD NTL 
Unequivocal  
+ 
Any  
= 
iCPD 
iUPD NL 
+ 
NLT 
≥5 mm iSoD  
NL NT 
Any  
= 
iCPD 
Worsening in Other Lesion Category 
iUPD TL 
≥20% SoD 
+ 
NTL 
Unequivocal  
= 
iCPD 
 
OR 
 
 
 
 
+ 
NL 
= 
iCPD 
iUPD NTL 
Unequivocal  
+ 
TL 
≥20% SoD 
= 
iCPD 
 
OR 
 
 
 
 
+ 
NL 
= 
iCPD 
Abbreviations: 
 increase 
iCPD, immune confirmed progressive disease 
iSoD, immune sum of diameters for new lesion target 
iUPD, immune unconfirmed progressive disease 
NTL, non target lesion 
NL, new lesion 
NL NT, new lesion non target 
NLT, new lesion target 
SoD, sum of diameters for all target lesions 
TL, target lesion 
 
 


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Table 5: Comparison Between RECIST 1.1 and iRECIST 
 
RECIST 1.1 
iRECIST 
Definition of measurable 
and non-measurable 
disease; numbers and 
site of target disease  
Measurable lesions are 
10 mm in diameter (15 mm 
for nodal lesions); maximum 
of 5 lesions (2 per organ); all 
other disease is considered 
non-target (must be 10 mm 
in short axis for nodal disease) 
No change from RECIST 1.1; however, new lesions 
are assessed as per RECIST 1.1 but are recorded 
separately on the case report form (but not included 
in the sum of lesions for target lesions identified at 
baseline) 
CR, PR, or SD 
Cannot have met criteria for 
progression before CR, PR, or 
SD 
Can have had iUPD (1 or more instances), but not 
iCPD, before iCR, iPR, or iSD 
Confirmation of CR or 
PR 
Required 
As per RECIST 1.1  
Confirmation of SD 
Not required 
Not required 
New lesions 
Result in progression; 
recorded but not measured 
New lesions should be assessed and categorized as 
measurable or non-measurable using RECIST 1.1. 
New lesions result in iUPD, but iCPD is only 
assigned on the basis of this category if at the next 
assessment, additional new lesions appear or an 
increase in size of new lesions is seen (5 mm for 
the sum of new lesion target or any increase in new 
lesion non-target); the appearance of new lesions, 
when none have previously been recorded, can also 
confirm iCPD.  
Confirmation of 
progression 
Not required (unless 
equivocal) 
The next imaging assessment should be performed 
at 4 weeks but 8 weeks after iUPD. Progression 
is confirmed if the next imaging assessment 
confirms a further increase in size of at least 5 mm 
in the lesion category in which progression was first 
identified, or progression in a lesion category that 
had not previously met RECIST 1.1 progression 
criteria, or development of new lesions. However, 
the criteria for iCPD (after iUPD) are not 
considered to have been met if iCR, iPR, or iSD 
criteria (compared with baseline and as defined by 
RECIST 1.1) are met at the next assessment after 
iUPD. The status is then reset and iCR, iPR, or iSD 
should be documented. 
 
Consideration of clinical 
status 
Not included in assessment 
Clinical stability is considered when deciding 
whether treatment is continued after iUPD 
Abbreviations: CR, complete response; iCPD, confirmed progression assigned using iRECIST; iCR, complete response 
assigned using iRECIST; iPR, partial response assigned using iRECIST; iSD, stable disease assigned using iRECIST; iUPD, 
unconfirmed progression assigned using iRECIST; PR, partial response; RECIST, Response Evaluation Criteria in Solid 
Tumors; SD, stable disease. 
 
Reference: Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials 
testing immunotherapeutics. Lancet Oncol. 2017;18:e143-e152. 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Phase 2, Non-randomized Open-label Study Examining the Effect of 
eFT508 in Patients with Advanced Castrate-resistant Prostate Cancer 
(CRPC) 
 
Protocol Number: 
eFT508-0009 
Investigational Product 
eFT508 (also referred to as Tomivosertib) 
Development Phase: 
2 
Sponsor: 
eFFECTOR Therapeutics, Inc 
11180 Roselle Street, Suite A 
San Diego, CA 92121 
United States 
Protocol Version Number: 
3.0 
Protocol Date: 
30 November 2018 
 
 
 
 
SAP Version: 
V1.0 
SAP Date: 
27 February 2020 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains information that is confidential and proprietary to eFFECTOR 
Therapeutics, Inc. (eFFECTOR) and is provided for the purpose of conducting a clinical trial 
for eFFECTOR. The contents of this document may be disclosed only to study personnel, the 
Institutional Review Board/Independent Ethics Committee, or duly authorized 
representatives of regulatory agencies for this purpose under the condition that they maintain 
confidentiality. The contents of this document may not be used in any other clinical trial, 
disclosed to any other person or entity, or published without prior written permission from 
eFFECTOR.  
 


eFFECTOR Therapeutics Inc. 
eFT508-0009  Statistical Analysis Plan                                                                                              Page 2 
 
Protocol: A Phase 2, Non-randomized Open-label Study Examining the 
Effect of eFT508 in Patients with Advanced Castrate-resistant Prostate 
Cancer (CRPC) 
 
 
Protocol Number: 
eFT508-0009 
Protocol Version: 
3.0 
SAP Version: 
Version 1.0 
 
This Statistical Analysis Plan has been reviewed and approved by: 
 
 
 
 
 
 
Mark Burch, Ph.D. 
Date 
Sr. Biostatistician 
Medpace, Inc. 
 
 
 
 
 
 
Lyon Gleich, MD 
 
Date 
Vice President, Medical Affairs 
Medpace Inc. 
 
 
 
 
 
 
Mark Densel 
 
Date 
Vice President, Program Management 
eFFECTOR Therapeutics, Inc. 
 
 
 
 


eFFECTOR Therapeutics Inc. 
eFT508-0009  Statistical Analysis Plan                                                                                              Page 3 
 
TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................................... 9 
2 
STUDY OBJECTIVES .................................................................................................................... 9 
3 
STUDY OVERVIEW ...................................................................................................................... 9 
3.1 
Study Design .......................................................................................................................... 9 
3.2 
Study Centers ....................................................................................................................... 10 
3.3 
Randomization and Blinding ................................................................................................ 10 
3.4 
Sample Size Determination .................................................................................................. 10 
3.5 
Duration of Study ................................................................................................................. 10 
3.6 
Schedule of Events ............................................................................................................... 11 
4 
ANALYSIS POPULATIONS ....................................................................................................... 15 
4.1 
Full Analysis Population ...................................................................................................... 15 
4.2 
Safety Population ................................................................................................................. 15 
5 
STUDY ASSESSMENTS ............................................................................................................. 15 
5.1 
Efficacy Assessments ........................................................................................................... 15 
5.1.1 
Clinical Response Assessment (iRECIST).............................................................. 15 
5.1.2 
Prostate-Specific Antigen (PSA) ............................................................................. 16 
5.1.3 
Bone Scan ................................................................................................................ 16 
5.1.4 
Other Efficacy Assessments .................................................................................... 16 
5.1.4.1 
Circulating Tumor Cells ..................................................................................... 16 
5.1.4.2 
P-eIF4E ............................................................................................................... 16 
5.2 
Safety Assessments .............................................................................................................. 17 
5.2.1 
Adverse Events ........................................................................................................ 17 
5.2.2 
Clinical Laboratory Evaluations .............................................................................. 18 
5.2.3 
Weight and Height .................................................................................................. 18 
5.2.4 
Vital Signs ............................................................................................................... 19 
5.2.5 
Electrocardiograms (ECGs) .................................................................................... 19 
5.2.6 
Physical Examinations ............................................................................................ 19 
5.2.7 
Eastern Cooperative Oncology Group .................................................................... 19 
5.2.8 
Prior and Concomitant Medications ........................................................................ 19 
5.3 
Pharmacokinetic Assessments ............................................................................................. 20 
6 
CLINICAL OUTCOME VARIABLES ......................................................................................... 20 
6.1 
Primary Efficacy Endpoint ................................................................................................... 20 
6.1.1 
Objective Response Rate ......................................................................................... 20 
6.1.2 
PSA Response Rate ................................................................................................. 20 
6.2 
Secondary Efficacy Endpoints ............................................................................................. 21 
6.2.1 
Progression Free Survival - iRECIST ..................................................................... 21 
6.2.1.1 
Censoring Rules for Progression Free Survival .................................................. 21 
6.2.2 
Progression Free Survival – PCWG2 ...................................................................... 22 
6.2.2.1 
Censoring Rules for PCWG2 PSA Progression Free Survival ........................... 23 
6.2.3 
Progression Free Survival – Bone ........................................................................... 23 


eFFECTOR Therapeutics Inc. 
eFT508-0009  Statistical Analysis Plan                                                                                              Page 4 
 
6.2.3.1 
Censoring Rules for Progression Free Survival – Bone ..................................... 24 
6.3 
Safety Endpoints .................................................................................................................. 24 
6.3.1 
Adverse Events ........................................................................................................ 24 
6.3.2 
Total Exposure to Tomivosertib .............................................................................. 24 
6.4 
Pharmacokinetics ................................................................................................................. 25 
7 
STATISTICAL ANALYSES ........................................................................................................ 25 
7.1 
General Statistical Considerations ....................................................................................... 25 
7.1.1 
Baseline Definition .................................................................................................. 25 
7.1.2 
Covariate Adjustment .............................................................................................. 26 
7.1.3 
Multicenter Studies ................................................................................................. 26 
7.1.4 
Multiple Comparisons ............................................................................................. 26 
7.1.5 
Handling of Dropouts or Missing Data ................................................................... 26 
7.1.6 
Examination of Subgroups ...................................................................................... 26 
7.1.7 
Interim Analysis ...................................................................................................... 26 
7.2 
Study Population Data.......................................................................................................... 27 
7.2.1 
Subject Disposition ................................................................................................. 27 
7.2.2 
Protocol Deviations ................................................................................................. 27 
7.2.3 
Demographics and Baseline Characteristics ........................................................... 27 
7.2.4 
Medical History ....................................................................................................... 28 
7.2.5 
Prior and Concomitant Medications ........................................................................ 28 
7.2.6 
Prior Cancer Therapies, Surgeries, and Radiation .................................................. 28 
7.3 
Efficacy Analyses ................................................................................................................ 29 
7.3.1 
Primary Efficacy Analyses ...................................................................................... 29 
7.3.1.1 
Objective Response Rate .................................................................................... 29 
7.3.1.2 
PSA Response Rate ............................................................................................ 29 
7.3.2 
Secondary Efficacy Analyses .................................................................................. 29 
7.3.2.1 
Progression Free Survival - iRECIST................................................................. 29 
7.3.2.2 
Progression Free Survival – PSA ....................................................................... 30 
7.3.2.3 
Progression Free Survival – Bone ...................................................................... 30 
7.3.3 
Exploratory Efficacy Analyses ................................................................................ 30 
7.3.3.1 
Circulating Tumor Cells ..................................................................................... 30 
7.3.3.2 
P-eIF4E ............................................................................................................... 30 
7.3.3.3 
Other Efficacy Analysis ..................................................................................... 31 
7.4 
Safety Analyses .................................................................................................................... 31 
7.4.1 
Extent of Exposure .................................................................................................. 31 
7.4.2 
Adverse Events ........................................................................................................ 31 
7.4.3 
Clinical Laboratory Evaluations .............................................................................. 32 
7.4.4 
Vital Signs ............................................................................................................... 32 
7.4.5 
Electrocardiograms.................................................................................................. 33 
7.4.6 
Performance Status .................................................................................................. 33 
7.4.7 
Other Safety Analyses ............................................................................................. 33 
7.5 
Pharmacokinetic Analysis .................................................................................................... 33 
8 
GENERAL INFORMATION ........................................................................................................ 33 


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8.1 
Statistical Software............................................................................................................... 33 
8.2 
Format of Tables, Listings, and Figures ............................................................................... 33 
9 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSIS......................................................... 34 
10 REFERENCES .............................................................................................................................. 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations and Definitions of Terms 
 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
aPTT 
Activated partial thromboplastin time 
ATC 
Anatomical therapeutic chemical 
BID 
Bis in die 
BMI 
Body mass index 
Bone PFS 
Bone Progression Free Survival by PCWG2 
iBOR 
Best objective response 
CI  
Confidence interval 
iCR 
Complete response 
CT 
Computed tomography 
CTC 
Circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
iCPD 
Confirmed disease progression assigned using 
iRECIST 
iUPD 
Unconfirmed disease progressoin assigned using 
iRECIST 
iRECIST 
Modified Response Evaluation Criteria in Solid 
Tumor in cancer immunotherapy trials 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
iNE 
Not evaluable 
iORR 
Objective response rate 
OS 
Overall survival 
PSA 
Prostate Specific Antigen 
PSA PFS 
Prostate Specific Antigen Progression Free Survival 
by PCWG2 
PCWG2 
Prostate Cancer Working Group 
PET 
Positron emission tomography 
iPFS 
Progression free survival based on iRECIST 
PK 
Pharmacokinetics 
PO 
Per os 
iPR 
Partial response 
PRR 
PSA Response Rate 
PT 
Preferred term 
SAE 
Serious adverse advent 
SAP 
Statistical Analysis Plan 


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eFT508-0009  Statistical Analysis Plan                                                                                              Page 7 
 
ABBREVIATION 
DEFINITION 
iSD 
Stable disease   
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
WHO 
World Health Organization 
 
 
 


eFFECTOR Therapeutics Inc. 
eFT508-0009  Statistical Analysis Plan                                                                                              Page 8 
 
Version History 
 
Version Date 
Version 
Description 
27 February 2020 
1.0 
Initial version 
 
 


eFFECTOR Therapeutics Inc. 
eFT508-0009  Statistical Analysis Plan                                                                                              Page 9 
 
1 
INTRODUCTION  
This Statistical Analysis Plan (SAP) describes the statistical methodology and analyses to be 
conducted for eFFECTOR Therapeutics, Inc. protocol eFT508-0009 (Version 3.0; 30 
November 2018).  Any deviations from this analysis plan will be substantiated by sound 
statistical rationale and will be documented in the final clinical study report. 
2 
STUDY OBJECTIVES 
Primary Objective: 
 To assess anti-tumor response of tomivosertib in advanced CRPC. 
Secondary Objectives: 
 To further characterize anti-tumor activity in terms of time-to-event data. 
 To characterize the safety, tolerability, and PK of tomivosertib. 
Exploratory Objectives:  
 To correlate efficacy with the characteristics of circulating tumor cells (CTCs) and P-
eIF4E status of available tumor tissue (archival or fresh). 
3 
STUDY OVERVIEW 
3.1 
Study Design 
This Phase 2 study examines the efficacy, safety, tolerability, and PK of tomivosertib in 
advanced CRPC patients who have documented PSA progression on treatment with 
apalutamide and/or abiraterone and/or enzalutamide for whom no suitable curative therapy 
exists. A Simon 2- stage minimax design (Simon 1989) will target the desired tumor 
response rate of tomivosertib monotherapy. Time-to-event parameters will also be collected. 
CTCs will be measured on all patients and efficacy parameters will be correlated with their 
presence/absence and with their particular characteristics (eg, presence of mutations and 
splice variants).  
Study drug will be administered in 4-week (28 day) treatment cycles. Patients will 
selfadminister tomivosertib orally (PO) at 200 mg BID. Study drug will be administered until 
disease progression (unless the patient is deriving clinical benefit, based on iRECIST 
[Seymour 2017 and http://recist.eortc.org/irecist/] and is clinically stable), unacceptable 
toxicity, the patient withdraws consent, the Investigator or Sponsor discontinues the patient, 
or the study is terminated. At the discretion of the Investigator, and with the Sponsor’s 
approval, patients who meet PSA progression criteria per PCWG2 may continue treatment 
with tomivosertib if the patient is perceived to be deriving clinical benefit. Patients who 
discontinue study drug permanently will remain on study for the acquisition of safety 
information for up to 30 days after the last dose of study drug, unless they withdraw consent 


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eFT508-0009  Statistical Analysis Plan                                                                                              Page 10 
 
for further follow-up, and for further collection of information regarding additional therapies 
for their cancer and survival.  
Safety assessments will include adverse event (AE) recording, physical examinations, vital 
sign measurements, ECGs, Eastern Cooperative Oncology Group (ECOG) performance 
status, and clinical safety laboratory tests (hematology, serum chemistry, thyroid function, 
coagulation, and urinalysis).  
Safety assessments will include AE recording, physical examinations, vital sign 
measurements, electrocardiograms (ECGs), Eastern Cooperative Oncology Group (ECOG) 
performance status, and clinical safety laboratory tests. AEs and laboratory abnormalities 
will be graded using the adult NCI CTCAE v 5.  
Efficacy assessments will include PSA evaluations on Day 1 of each cycle and radiographic 
examinations (including bone scan) every 8 ± 1 weeks for 1 year, then every 12 ± 1 weeks 
until confirmed progression. Response will be evaluated using iRECIST.  
Blood samples for PK analysis will be collected, and PK data will be assessed and correlated, 
as appropriate, with efficacy findings. 
3.2 
Study Centers 
The study will be conducted at up to 10 sites globally.   
3.3 
Randomization and Blinding 
This is a non-randomized, open-label study; therefore, the Sponsor, Investigator, and patient 
will know the study drug being administered. 
3.4 
Sample Size Determination 
Total sample size will include up to 27 evaluable patients.  
Simon’s 2-stage design will be used to evaluate the tumor response rate. The null hypothesis 
that the true response rate is 5% will be tested against a one-sided alternative. In the first 
stage, 13 patients will be accrued. If there are no responses in these 13 patients after a 
minimum of 16 weeks of exposure to tomivosertib, the study will be stopped.  
Otherwise, 14 additional evaluable patients will be accrued for a total of 27 patients. The null 
hypothesis will be rejected if 4 or more responses are observed in 27 patients. Enrollment of 
approximately 30 patients is planned to have 27 evaluable patients to target a tumor response 
rate of ≥20%. 
3.5 
Duration of Study 
The overall duration of the study is anticipated to be approximately 2 years from the first 
patient’s first visit until the last patient’s last visit. For regulatory reporting purposes, the end 


eFFECTOR Therapeutics Inc. 
eFT508-0009  Statistical Analysis Plan                                                                                              Page 11 
 
of the study is defined as the date the last patient completes the End-of-Treatment Visit or the 
last patient completes 6 months of therapy, whichever occurs first. 
3.6 
Schedule of Events 
The Schedule of Events is presented in Table 1. 


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Table 1: Schedule of Events  
 
 
 
 


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[a]  Informed consent to be obtained before other study procedures are performed. 
[b]   Medical history to include recording of cancer history, previous anticancer therapies (including prior hormonal interventions), surgical history, past and ongoing medical 
conditions, and review of systems 
[c]   Height to be obtained at Screening only. 
[d]  Vital signs (blood pressure, pulse, temperature) will be collected with the patient in a supine position. 
[e]   12-lead ECGs will be obtained with patients in a supine position. ECGs will be collected at Screening, Day 1 of every cycle, and at the end of treatment. 
[f]  Hematology testing will include hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils; 
platelet count. On tomivosertib clinic dosing days, predose samples should be obtained and results assessed before tomivosertib administration. 
[g]   Serum chemistry studies will include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphorus, magnesium, total protein, albumin, ALT, 
AST, ALP, CK, LDH, total bilirubin, uric acid. On tomivosertib clinic dosing days, predose samples should be obtained and results assessed before tomivosertib administration. 
Serum testosterone to be confirmed at baseline as ≤1.73 nmol/L (50 ng/dL). 
[h]  PSA testing –At Screening, Day 1 of every cycle, and at the end of treatment. PSA response by PCWG2 criteria must be confirmed ≥4 weeks later. The blood sample is 
collected before the morning dose. 
[i]   Circulating Tumor Cells will be assessed at Screening or predose on Cycle 1 Day 1, Day 1 of every cycle, and at the end of treatment. 
[j]  Coagulation studies will include PT, aPPT, INR at Screening and end of treatment Visit.  
[k]   Urinalysis will include specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase as assessed by dipstick. A microscopic 
urinalysis evaluating white blood cells, red blood cells, epithelial cells, bacteria, cast and crystals, will be performed only as needed. On tomivosertib clinic dosing days, predose 
samples should be obtained and assessed before tomivosertib administration. To be performed at Screening, Cycle 1 Day 1, Cycle 3 Day 1, and every odd cycle.  
[l]  Blood samples will be collected before the tomivosertib morning dose and at 3 ±1 hours after the tomivosertib morning dose. The date and actual nominal time of blood 
sampling must be recorded. If a patient mistakenly takes tomivosertib at home on days when it should be administered at the site for PK sampling, blood samples for tomivosertib 
PK should not be collected on those days, and the patient should return at the next available time for tomivosertib administration at the clinical site with tomivosertib PK sampling. 
[m]   The predose sample should be obtained at 12 ± 1 hours postdose from the Cycle 1 Day 14 tomivosertib evening dose. The time of the tomivosertib Cycle 1 Day 14 evening 
dose administered at home, prior to PK blood collection, should also be recorded. 
[n]   The predose sample should be obtained at 12 ± 1 hours postdose from the Cycle 1 Day 28 tomivosertib evening dose. The time of the tomivosertib Cycle 1 Day 28 evening 
dose administered at home, prior to PK blood collection, should also be recorded.  
[o]   Cycles 4 and 8 only. The predose sample should be obtained at 12 ± 1 hours postdose from Cycle 3 Day 28 and Cycle 7 Day 28 tomivosertib evening doses (ie, predose on 
Cycle 4 Day 1 and Cycle 8 Day 1). The time of the tomivosertib Cycles 3 and 7 Day 28 evening doses administered at home, prior to PK blood collection, should also be recorded. 
3 ±1 hour postdose samples will also be collected on Day 1 of Cycles 4 and 8.  
[p]  Physical examination is required at Screening and Cycle 1 Day 1. A physical assessment, which can be done by a research nurse, may be performed at other visits.  
[q]  Radiology examination will include CT (and may include PET, if relevant) or MRI imaging of chest, abdomen, and pelvis. The same method of assessment (CT, CT/PET, 
MRI) and the same technique should be used to characterize each identified and reported lesion at Screening and while on study. Evaluations are to be performed during Screening 
within 28 days prior to the initiation of study therapy; then every 8 ± 1 weeks for 1 year, then every 12 ± 1 weeks until confirmed progression. An end-of-treatment radiology 
assessment should be performed unless the patient already has radiographic confirmation of PD ≤4 weeks prior to permanent study drug discontinuation. Bone scans will be 
performed at Screening, every 8 ± 1week for 1 year, then every 12 ± 1week until confirmed progression. New bone lesions are to be confirmed with repeat scan ≥ 6 weeks later.  
[r]   Posttherapy safety assessment will be performed after permanent cessation of tomivosertib to follow patients for any drug-related adverse events and/or ongoing serious 
adverse events. Patients will be followed for ≥30 days or until those events have resolved or become stable, whichever occurs later. Follow-up may be obtained in person or by 
telephone contact.  
[s]  Long-term follow-up information will be obtained in all surviving patients who permanently discontinue study therapy. For patients who discontinue study treatment without 
radiologic disease progression, every effort should be made to continue monitoring disease status by tumor imaging per standard of care until the start of a new anticancer 
treatment, disease progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first. Data on post-study therapies for the cancer, and on survival 
will be collected. Such information may be collected at ~3- to 6-month intervals at the Sponsor’s discretion through 18 months. This long-term follow-up information will be 
gathered during routine clinic visits, other study site contact with the patients, or via telephone or e-mail with the patients/caregivers or referring physician offices. These data will 
be collected in the source documents (eg, patient medical record) and transcribed to a specific eCRF.  


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[t] This assessment may be performed at Screening or Cycle 1 Day 1 prior to first dose of tomivosertib.  
 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea 
nitrogen; CK, creatine kinase; CT, computed tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case report form; INR, 
international normalized ratio; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PCWG2, Prostate-Specific Antigen Working Group 2; PD, progressive disease; 
PET, positron emission tomography; PK, pharmacokinetics; PSA, prostate-specific antigen; PT, partial thromboplastin time. 


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eFT508-0009 Statistical Analysis Plan 
Page 15 
 
4 
ANALYSIS POPULATIONS 
This section defines the analysis populations to be used for the planned statistical analyses.  
4.1 
Full Analysis Population 
Full Analysis Population: The Full Analysis Population will include all enrolled patients. 
This analysis set will be used for all disposition, demographic, and disease history 
summaries.  
4.2 
Safety Population 
Safety Population: The Safety Population will include all enrolled patients who receive 1 
dose of tomivosertib. This analysis set will be used for all safety and efficacy analyses.  
Summaries based on the full analysis population may also be produced for the safety 
population if the populations differ.  
5 
STUDY ASSESSMENTS 
5.1 
Efficacy Assessments 
5.1.1 
Clinical Response Assessment (iRECIST) 
The treatment response for each subject will also be determined at the timepoints in the 
Schedule of Events using iRECIST guidelines. At each assessment, subjects will be assigned 
a treatment response by the Investigator from among the following iRECIST categories: 
 Complete Response (iCR) 
 Partial Response (iPR) 
 Stable Disease (iSD) or non-iCR/non-iUPD (in case of no target disease) 
 Unconfirmed Progressive Disease (iUPD) 
 Confirmed Progressive Disease (iCPD) 
 Not Evaluable (iNE) 
In addition, if the iRECIST assessment is considered iCPD, then the confirmed progressive 
disease will be classified according to one (or more) of the following subcategories 
 Further increase in sum of target lesions >=5mm 
 Further increase in sum of new target lesions >= 5mm 
 Another new lesion 


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 Significant further increase in non-target lesions.  
Note that subjects with no target disease at baseline may be enrolled on study and assigned to 
the non-iCR/non-iUPD category for overall response in place of iSD on the basis of the non-
target lesion assessment.  
Further details regarding iRECIST response assessments are given in Protocol Section 13.6. 
5.1.2 
Prostate-Specific Antigen (PSA) 
PSA levels will be assessed locally at Screening, on Day 1 of every cycle, and at end of 
treatment. Tumor response will be evaluated using PSA levels as a co-primary endpoint. PSA 
response is defined further in Section 6.1.2.  
A secondary efficacy endpoint is Prostate Cancer Working Group (PCWG2) PSA 
progression-free survival (PSA progression defined as a ≥25% increase in PSA from nadir or 
baseline [and by ≥2 ng/mL] and requiring confirmation ≥3 weeks later).  
PCWG2 recommends continuing treatment with newly initiated prostate cancer therapies for 
at least 12 weeks without clinical evidence for disease progression. 
Details for the derivation of PSA PFS are given in Section 6.2.2 and Scher et al. (2008). 
5.1.3 
Bone Scan 
Bone scans will be performed using standard local radionuclide imaging. The same technique 
should be used to evaluate the presence of bone lesions during screening and throughout the 
study. Bone scans will be performed at screening every 8 ± 1 weeks for 1 year, then every 12 
± 1 weeks until progression. New bone lesions are to be confirmed with repeat scan 6 or 
more weeks later. A secondary efficacy endpoint is Bone PFS as defined by PCWG2. 
Details for the derivation of Bone PFS are given in Section 6.2.3 and Scher et al. (2008).  
5.1.4 
Other Efficacy Assessments 
5.1.4.1 
Circulating Tumor Cells 
CTCs will be assessed in blood collected at Screening or Cycle 1 Day 1 prior to first dose of 
tomivosertib, Day 1 of every cycle, and at the end of treatment using the Oncotype DX AR-
V7 Nucleus. 
5.1.4.2 
P-eIF4E 
Tumor tissue (archival or fresh), if available will be obtained at Screening to evaluate P-
eIF4E status. Baseline archival tumor tissue if available should be from a biopsy procedure 
performed closest to the start of study treatment. If archival tissue is unavailable, tissue 
sample from a fresh biopsy may be submitted, if patient agrees to the this optional procedure. 


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5.2 
Safety Assessments 
Safety assessments will include adverse event reporting, clinical laboratory evaluations 
(including chemistry and hematology), vital signs, Electrocardiograms (ECGs), physical 
examinations, ECOG performance status evaluation, and prior and concomitant medication 
reporting.  
5.2.1 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical 
investigation subject administered a study drug; the event does not necessarily have a causal 
relationship with study drug or usage.  
All AEs, regardless of causality or seriousness, will be recorded from the time the patient takes 
the first dose of study drug until 30 days after the last dose of study drug. After discontinuing 
study drug, patients will be followed until the later of either 30 days after the last dose of study 
drug or until resolution/stabilization of any ongoing drug-related AEs.  
AEs that start during or after initiating study drug or that worsen after study drug initiation will 
be considered treatment-emergent adverse events (TEAEs). Study drug initiation will be 
considered the first dose date of tomivosertib. AEs that occur between the time the subject 
signs the informed consent form and the start of study drug will be considered pre-treatment 
AEs.  
AEs will be coded using the Medical Dictionary for Regulatory Activities  as described in the 
Data Management Plan. The severity of all adverse events will be graded according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5. If an 
AE is not given a severity grade it will not be imputed.  
The relationship of an AE to the administration of tomivosertib will be classified as possibly 
related or unlikely related as follows.  
 
Table 2: Relationship of an Adverse Event to Study Drug 
Relationship 
Description 
Possibly Related 
The AE is known to occur with the study drug, there is a 
reasonable possibility that the study drug caused the AE, or 
there is a temporal relationship between the study drug and 
event. Reasonable possibility means that there is evidence to 
suggest a causal relationship between the study drug and the 
AE.  


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Unlikely Related 
There is not a reasonable possibility that the administration of 
the study drug caused the event, there is no temporal 
relationship between the study drug and event onset, or an 
alternate etiology has been established.  
5.2.2 
Clinical Laboratory Evaluations 
Clinical laboratory assessments will be performed at the visits and times specified in the 
Schedule of Events (Table 1).  
The following clinical laboratory parameters will be evaluated during the study.  
Table 3: Diagnostic and Safety Laboratory Assessments and Parameters 
Laboratory Test 
Parameters 
 
Serum Chemistry 
• Sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, phosphorus, magnesium, total protein, albumin, 
ALT, AST, ALP, CK, LDH, total bilirubin, uric acid. 
• Serum testosterone to be confirmed at baseline as ≤1.73 nmol/L 
(50 ng/dL) 
Hematology 
• Hematocrit, hemoglobin, erythrocyte count 
• Absolute counts of leukocytes, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils 
• Platelet count. 
Coagulation 
• Prothrombin time, Activated partial thromboplastin time (aPTT), 
INR 
Urinalysis 
• Dipstick: specific gravity, pH, protein, glucose, ketones, bilirubin, 
urobilinogen, blood, nitrite, leukocyte esterase 
• Microscopy: white blood cells, red blood cells, epithelial cells, 
bacteria, casts and crystals (to be performed as needed) 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; 
AST, aspartate aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; INR, international normalized ratio; LDH, 
lactate dehydrogenase; PT, prothrombin time. 
5.2.3 
Weight and Height 
Weight (kg or lb) and Height (cm or inches) will be assessed at Screening.  


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Weight will also be assessed after Screening at the times indicated in the Schedule of Events.  
5.2.4 
Vital Signs 
Vital signs will be assessed at the times indicated in the Schedule of Events.  
Vital signs measurements including systolic and diastolic blood pressure (mmHg), pulse rate 
(beats/min), and temperature (ºC or ºF).  
5.2.5 
Electrocardiograms (ECGs) 
A 12-lead Electrocardiogram will be completed at the times indicated in the Schedule of 
Events.  The ventricular rate (beats/min), QRS interval (msec), QT interval (msec), QTcF 
interval (msec), PR interval (msec), RR interval (msec), and overall interpretation (Normal, 
abnormal clinically significant, abnormal not clinically significant) will be recorded.   
5.2.6 
Physical Examinations 
Physical Examinations will be performed at the times indicated in the Schedule of Events. 
Any abnormalities will be noted as AEs or medical history and corresponding information 
will be recorded.  
5.2.7 
Eastern Cooperative Oncology Group  
Eastern Cooperative Oncology Group (ECOG) performance sttaus will be assessed at the 
times indicated in the Schedule of Events. The ECOG performance status on a scale from 0-4 
will be recorded. 
5.2.8 
Prior and Concomitant Medications 
All medications taken by subjects between signing the informed consent form and the End of 
Therapy Visit will be recorded. Thereafter, only concomitant medications taken for the 
treatment of an AE will be recorded for up to 30 days after the last dose of study therapy. 
Concomitant medications include all prescription, over-the-counter, IV infusions, 
transfusions, and alternative medications (including herbal products and vitamins). 
Concomitant therapy (eg, radiation therapy) and surgery should also be recorded. 
All medications will be recorded on the electronic case report form (eCRF) and will be coded 
using the World Health Organization Drug Dictionary (WHO-DDE B2, September 2018 or 
later as described in Data Management Plan).   
Prior medications are defined as medications that were started prior to the first dose date of 
study drug. Concomitant medications are medications that were taken on or after the first 
dose date of study drug. A medication can be both prior and concomitant if it was started 
prior to the first dose date of study drug and continued during the treatment period. 


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The medication administered, indication, dose, route, frequency, and start and stop dates will 
be recorded in the eCRF.  
5.3 
Pharmacokinetic Assessments 
Blood samples for Pharmacokinetic (PK) assessments of tomivosertib and will be obtained at 
the times indicated in the Schedule of Events.  
6 
CLINICAL OUTCOME VARIABLES 
This section describes the clinical outcomes and derivation of variables considered for this 
study.  
6.1 
Primary Efficacy Endpoint 
6.1.1 
Objective Response Rate 
The primary efficacy endpoint will be the Objective Response Rate (iORR) using iRECIST 
based on the Safety Population.  
In general, iBOR will be determined based on the overall visit responses from each iRECIST 
assessment by the Investigator. iBOR is defined as the best response (in the order of  iCR, 
iPR, iSD, iUPD, and iCPD using iRECIST) a subject has experienced following the first dose 
of study treatment, but prior to and including progression or the last evaluable assessment in 
the absence of disease progression. The iCR/iPR must be confirmed at least 4 weeks after the 
response is first documented to be included. To be counted as a best response of iSD or better 
the assessment should occur at least 7 weeks after the frst dose of tomivosertib (8 weeks 
minus 1 week for the allowed visit window).   
Subjects with no evaluable iRECIST assessments after first dose of tomivosertib will be 
assigned to the NE category, unless the reason for discontinuation is clinical progression. If a 
subject has no evaluable iRECIST assessments after first dose of tomivosertib and 
discontinues due to clinical progression, the BOR will be assigned to the iUPD category. 
Using iRECIST, the iORR is defined as the proportion of subjects whose iBOR is an iCR or 
iPR.  
6.1.2 
PSA Response Rate 
A co-primary efficacy endpoint will be the PSA Response Rate (PRR) using the PCWG2 
criteria based on the Safety Population.  
A PSA responder is a subject with a  ≥50% PSA decline from baseline at any time point after 
therapy and maintained for ≥4 weeks. The initial response will be considered to meet the 


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requirement as maintained for 4 weeks if the next PSA assessment, occurring at least 4 weeks 
after the initial response assessment, also shows a ≥50% PSA decline from baseline.   
If the response is not maintained for at least 4 weeks it will not be included in the calculation 
of the PRR. Subjects with no baseline PSA assessment or missing post-baseline PSA 
assessment will be included in the calculation of the PRR.  
6.2 
Secondary Efficacy Endpoints 
6.2.1 
Progression Free Survival - iRECIST 
iPFS is defined as the interval from the start of study therapy until disease progression or 
death from any cause (whichever occurs first). Disease progression may be radiological 
progression (iUPD per iRECIST which is later confirmed as iCPD) or clinical progression. 
The start of study therapy is the first dose date of tomivosertib.  
Using iRECIST, iPFS will be calculated as:  
 iPFS (days) = Date of iUPD (radiological progression), clinical progression, or death 
(whichever occurs first) – first dose date of tomivosertib + 1 
Radiological progression will be based on the Investigator assessment using iRECIST. In 
order to count in the calculation for iPFS the iUPD should be confirmed as iCPD at the next 
assessment.  
If iUPD occurs but is disregarded because of later iSD, iPR, or iCR, that iUPD date should 
not be used as the progression event date. To be as conservative as possible, in the the case 
that an assessment of iUPD is recorded and no subsequent evaluable iRECIST assessments 
are recorded then the iUPD event will be treated as confirmed in the calculation of iPFS.  
For example, if progression is not confirmed and there is no subsequent iSD, iPR, or iCR, 
then the iUPD date should still be used (i.e. treated as confirmed)  in the following scenarios: 
if the patient stops protocol treatment because he was not judged to be clinically stable, or no 
further response assessments are done (because of patient refusal, protocol non-compliance, 
or patient death); the next timepoint responses are all iUPD and iCPD never occurs; or the 
patient dies from his cancer. 
6.2.1.1 
Censoring Rules for Progression Free Survival  
The following rules will be applied for iPFS based on iRECIST.  
Subjects who have not had radiological progression (i.e. a response of iUPD using iRECIST 
that is confirmed iCPD at the next iRECIST assessment), have not experienced clinical 
progression, or died at the time of analysis will be censored at the time of the last response 
assessment.  However, if the subject experiences progression (either clinical or radiological) 


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or dies after 2 or more missed visits, the subject will be censored at the time of the latest 
response assessment prior to the two missed visits. The length of time for two missed visits 
will depend on the scheduled visit interval and will include the visit window. For example, 
this will be calculated as 18 weeks during the first year of follow up as assessments are 
scheduled 8 weeks apart with visit window of one week. In addition, subjects that do not 
have disease progression but begin subsequent anticancer therapy will be censored on the 
date the subsequent anticancer therapy is started.   
If the subject has no evaluable visits or does not have a baseline assessment, they will be 
censored at Day 1. In the event that a subject has no evaluable post-baseline iRECIST 
assessment but discontinues due to clinical progression, the date of clinical progression will 
be considered the event date.  
The iPFS time will be derived based on scan/assessment dates and not visit dates to 
determine radiological progression.  Assessments/scans contributing towards a particular 
visit may be performed on different dates.  The following rules will be applied for this 
calculation: 
 Date of radiological progression will be determined based on the earliest of the 
assessment/scan dates of the component that triggered the progression (iUPD using 
iRECIST that is confirmed iCPD at the next assessment, or iUPD and subsequent 
discontinuation in absence of further iRECIST assessment).   
 When censoring a subject for iPFS, the subject will be censored at the latest of the 
assessment/scan dates contributing to a particular overall visit assessment. 
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of iPFS. 
6.2.2 
Progression Free Survival – PCWG2 
PCWG2 PSA Progression Free Survival (PSA PFS) is defined as the interval from the start 
of study therapy until the date PSA progression is first observed. The start of study therapy is 
the first dose date of eFT508. 
PSA progression is defined as a ≥25% increase in PSA from nadir or baseline [and by ≥2 
ng/mL] and requiring confirmation ≥3 weeks later.  
PCWG2 PSA PFS will be calculated as:  
 PSA PFS (days) = Date of PSA Progression – first dose date of tomivosertib + 1 


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In the event that a subject experiences initial PSA progression and has no further PSA 
assessments, the PSA progression will be considered confirmed for the calculation of 
PCGW2 PSA PFS.  
6.2.2.1 
Censoring Rules for PCWG2 PSA Progression Free Survival 
The following rules will be applied for PSA PFS.   
Subjects who have not had PSA progression will, unless otherwise specified, be censored at 
the time of the last PSA assessment.  However, if the subject experiences PSA progression 
after 2 or more missed PSA assessments, the subject will be censored at the time of the latest 
PSA assessment prior to the two missed visits.  
The length of time for two missed visits will depend on the follow-up timeline and will 
include the visit window.  
In addition, subjects that do not have PSA progression but begin subsequent anticancer 
therapy will be censored on the on the date the subsequent anticancer therapy is started .    
If the subject has no evaluable post-baseline PSA assessment or does not have a baseline 
assessment, the subject will be censored on Day 1. To be as conservative as possible, in the 
event that a subject may be censored for multiple reasons, the earlier censoring date will be 
used. 
6.2.3 
Progression Free Survival – Bone 
Bone Progression Free Survival (Bone PFS) is defined as the interval from the start of study 
therapy until bone progression. The start of study therapy is the first dose date of 
tomivosertib. 
Bone PFS will be calculated as:  
 Bone PFS (days) = Date of Bone progression – First dose date of tomivosertib + 1 
Bone progression is defined as the presence of 2 or more new bone lesions as well as a 
confirmatory scan performed 6 or more weeks later that shows additional new lesions. 
Bone progression via PCWG2 should be confirmed at a subsequent visit after initial 
progresion. When progression is documented on the confirmatory scan, the date of bone 
progression is the date of the first scan showing 2 or more new bone lesions. If a later 
assessment occurs which does not confirm the progression the event will not be counted.   
To be as conservative as possible, in the event that a subject has an initial assessment of bone 
progression and no further bone assessments (e.g. the subject discontinues the study prior to 
confirmation) then the progression will be considered confirmed.  


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6.2.3.1 
Censoring Rules for Progression Free Survival – Bone 
The following censoring rules will be applied for Bone PFS based on the PCWG2 bone 
assessment. 
Subjects who have not had bone progression will, unless otherwise specified, be censored at 
the time of the last bone scan assessment.  However, if the subject experiences bone 
progression after 2 or more missed bone scan assessments, the subject will be censored at the 
time of the latest bone scan assessment prior to the two missed visits.  
The length of time for two missed visits will depend on the follow-up timeline and will 
include the visit window. For example, this will be calculated as 18 weeks during the first 
year of follow up as assessments are scheduled 8 weeks apart with visit window of one week.  
In addition, subjects that do not have bone progression but begin subsequent anticancer 
therapy will be censored on the date the subsequent anticancer therapy is started.   
If the subject has no evaluable post-baseline PCWG2 bone assessment or does not have a 
baseline assessment, the subject will be censored at Day 1. To be as conservative as possible, 
in the event that a subject may be censored for two reasons above, the earlier censoring date 
will be used.  
6.3 
Safety Endpoints 
6.3.1 
Adverse Events 
Adverse Events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
MedDRA (v21.0 or later). The severity of all adverse events will be graded according to NCI 
CTCAE version 5. All AEs, regardless of causality or seriousness, will be recorded from the 
time the patient takesthe first dose of study drug until 30 days after the last dose of study drug. 
After discontinuingstudy drug, patients will be followed until the later of either 30 days after 
the last dose of study drug or until resolution/stabilization of any ongoing drug-related AEs.   
6.3.2 
Exposure to Tomivosertib 
The duration of tomivosertib treatment will be calculated as: 
 Duration of tomivosertib treatment (days) = Last dose date of tomivosertib – First 
dose date of tomivosertib + 1  
The actual exposure to tomivosertib will be calculated as: 
 Total exposure to tomivosertib (days) = Last dose date of tomivosertib – First dose 
date of tomivosertib – cumulative days of dose interruptions + 1 


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The duration of each dose interruption is defined as: 
 Duration of dose interruption = End date of interruption – Start date of interruption + 
1 
The cumulative days of dosing interruptions is defined as the sum of the duration of dose 
interruptions.  
If start/stop dates of dosing are missing after querying, the duration of treatment interruption 
will be treated as 1 day. In the case of a treatment interruption, interruptions occurring after 
the last dose date will not be considered in the calculation of total exposure to tomivosertib. 
6.4 
Pharmacokinetics 
The pharmacokinetics of tomivosertib will be assessed from blood samples taken at time 
indicated in the Schedule of Events. If applicable in the future, additional details regarding 
the PK parameters for tomivosertib may be described in a standalone PK analysis plan.  
7 
STATISTICAL ANALYSES 
This section describes the statistical analyses to be conducted in relation to the primary, 
secondary, and exploratory objectives of the study.  
7.1 
General Statistical Considerations 
All analyses will be performed using SAS® Version 9.3 or higher.  
Unless specified otherwise, the analyses of data collected will be descriptive and summaries 
will be presented for all subjects in a given analysis population. Statistical analyses will be 
descriptive and no formal hypothesis testing or comparative analyses between treatment arms 
will be performed. Confidence intervals (CIs) will be constructed at the 95% confidence level 
where appropriate.  
For continuous variables, the number of observations (n), mean, standard deviation, median, 
minimum, and maximum will be provided as summary statistics. For categorical variables, 
the frequency and percentage in each category will be displayed.   
Comprehensive data listings of datasets will be generated.  By-subject data listings of clinical 
trial data will include enrolled subjects.  
7.1.1 
Baseline Definition 
Unless stated otherwise, the baseline value is defined as the last observed measurement, 
whether scheduled or unscheduled, prior to the first dose of tomivosertib.  
Study Day 1 will be considered as the date of the first dose of tomivosertib.  


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7.1.2 
Covariate Adjustment 
No adjustment for other covariates is planned.  
7.1.3 
Multicenter Studies 
The center effect will not be considered for this study. 
7.1.4 
Multiple Comparisons 
Hypothesis testing may be performed for selected pharmacodynamic and efficacy endpoints. 
Inflation of the Type 1 error rate is a concern because this study defines two co-primary 
endpoints. 
Any statistically significant findings will be considered hypothesis generating for future 
studies. Therefore, no multiple comparisons adjustment will be applied to the efficacy 
analysis. 
7.1.5 
Handling of Dropouts or Missing Data 
Unrecorded data values will be recorded as missing. Only recorded (i.e. complete) data values 
will be used for statistical analyses. In general, invalid or missing values will not be imputed 
unless stated otherwise.  
In cases of missing or incomplete dates (e.g. AEs and concomitant medications), the missing 
component(s) will be assumed as the most conservative value possible. For example, AEs with 
missing start dates, but with stop dates either overlapping into the treatment period or missing, 
will be counted as treatment-emergent, taking the worst-case approach. When partial dates are 
present in the data, both a partial start date and/or a partial stop date will be evaluated to 
determine whether it can be conclusively established that the AE started prior to the start of 
study drug or ended prior to the start of study drug. If the above cannot be conclusively 
established based on the partial and/or present dates, then the AE will be considered as 
treatment-emergent. Actual data values as they appear in the original eCRFs will be presented 
in the data listings. 
To be conservative in the case of missing causality assessment for AEs after data querying, 
AEs will be assumed to be related to tomivosertib.  
7.1.6 
Examination of Subgroups 
There is no planned subgroup analysis. 
7.1.7 
Interim Analysis 
No formal interim analysis is planned. Safety data will be monitored on an ongoing basis.  


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Simon’s 2-stage design will be used to evaluate the tumor response rate. The null hypothesis 
that the true response rate is 5% will be tested against a one-sided alternative. In the first 
stage, 13 patients will be accrued. If there are no responses in these 13 patients after a 
minimum of 16 weeks of exposure to tomivosertib, the study will be stopped. Otherwise, 14 
additional evaluable patients will be accrued for a total of 27 patients. The null hypothesis 
will be rejected if 4 or more responses are observed in 27 patients. Enrollment of 
approximately 30 patients is planned to have 27 evaluable patients to target a tumor response 
rate of ≥20%. 
After enrollment of the first stage, it was decided by the sponsor to not continue enrollment 
of additional subjects into the study due to lack of observed response in accordance with the 
planned Simon 2-stage design.  
7.2 
Study Population Data 
7.2.1 
Subject Disposition 
Subject disposition will be summarized for the Full Analysis Population. 
The following subject disposition categories will be summarized: 
 Subjects who enrolled; 
 Subjects who received assigned treatment; 
 Subjects discontinued from study treatment; 
 Subject follow-up status at last follow-up visit; and 
 Subjects who terminated the study. 
For subjects who discontinued study treatment and subjects who terminated the study, a 
summary will be provided by reason for discontinuation or termination. The number of 
subjects discontinuing study treatment due to clinical progression will be summarized.  
The total number of subjects in each defined analysis population will be tabulated. 
Subject disposition data will be listed by subject.  
7.2.2 
Protocol Deviations 
Protocol deviations deemed reportable in the the clinical study report (CSR) per the study 
Protocol Deviation Plan will be listed by subject. 
7.2.3 
Demographics and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented using the 
Full Analysis Population.  


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Demographic characteristics may include, but are not limited to: age, sex, race, ethnicity, body 
weight, height, and body mass index (BMI).  
Cancer history will be collected during the Screening Period and summarized for the Full 
Analysis Population. Continuous variables including time from original prostate cancer 
diagnosis (months) and time from current prostate cancer diagnosis will be summarized with 
descriptive statistics. Categorical variables including original stage, current stage (overall, 
tumor, node, and metastasis), grade, primary tumor location, Gleason score, and prostate 
adenocarcinoma type will be summarized.  
7.2.4 
Medical History 
Medical history will be collected during the Screening Period. The reported medical history 
terms will be coded using the MedDRA (v21.0 or later as described in the Data Management 
Plan).  
Summary tables of medical history terms may be produced. Medical history will be listed.  
7.2.5 
Prior and Concomitant Medications 
All medications taken by subjects between signing the informed consent form and the End of 
Therapy Visit will be recorded. Only concomitant medications taken for the treatment of an 
AE will be recorded for up to 30 days after the last dose of study therapy.  
If warranted after data review, prior and concomitant medications may be summarized by 
System Organ Class and Preferred Term. In this case, a subject will be counted only once 
within an ATC classification but may contribute to two or more preferred terms in the same 
classification. 
Prior and concomitant medications will be listed.  
7.2.6 
Prior Cancer Therapies, Surgeries, and Radiation  
The number and percentage of patients with previous cancer therapy/medications will be 
summarized by line of therapy and best overall response to all prior treatments for the Full 
Analysis Population. The reported cancer therapy/medication terms will be coded using WHO 
Drug Dictionary (WHO-DDE B2, Version September 2018 or later). Prior cancer 
therapies/medications may be summarized by Anatomical Therapeutic Chemical (ATC) and 
preferred term. In this case, a subject will be counted only once within an ATC classification 
but may contribute to two or more preferred terms in the same classification.  
Prior cancer therapy, surgery, and radiation data will be listed.  


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7.3 
Efficacy Analyses 
Efficacy analyses described in this section will performed using the Safety Population. No 
sensitivity analysis is planned. Additional listings of efficacy data may be generated.  
7.3.1 
Primary Efficacy Analyses 
7.3.1.1 
Objective Response Rate 
The primary analysis will involve analysis of the iORR. The point estimate of the and iORR 
along with the exact Clopper-Pearson 95% CI will be presented.  Subjects who do not have 
sufficient baseline and on-study tumor assessments to characterize response (i.e. who have a 
BOR of iNE) will be included in the denominator for the calculation of the iORR.  
The best objective response (iBOR) will also be tabulated show the number and percentage 
of subjects in each response category.  
In addition, for subjects that have confirmed disease progression (iCPD) using iRECIST the 
type of disease progression will be tabulated. The following categories for disease 
progression will be summarized: 
 Further increase in sum of target lesions >=5mm 
 Further increase in sum of new target lesions >=5mm 
 Another new lesion 
 Significant further increase in non-target lesions –unequivocal increase 
7.3.1.2 
PSA Response Rate 
The co-primary analysis will involve analysis of the PRR. The point estimate of the PRR 
along with the exact Clopper-Pearson 95% CI will be presented. Subjects that do not have 
baseline or post-baseline PSA assessments will be included in the denominator for the 
calculation of the PRR.  
 
In addition, on-study PSA assessments will be listed.  Other data, such as percentage change 
from baseline may be listed. Other table summaries may be produced if data warrant.  
 
PSA analysis may also include additional graphical summaries as appropriate (e.g. spider 
plot, waterfall plot).  
7.3.2 
Secondary Efficacy Analyses 
7.3.2.1 
Progression Free Survival - iRECIST 
iPFS will be estimated using the Kaplan-Meier method.  


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The number and percentage of subjects experiencing a iPFS event and the type of event 
(clinical progression, radiological progression, or death) and subjects censored will be 
summarized. The Kaplan-Meier estimate of the median iPFS and Brookmeyer-Crowley 95% 
CI will be presented (Brookmeyer and Crowley 1982). 
Kaplan-Meier plots of iPFS will be presented.  
The analysis of iPFS will be based on the iRECIST Investigator overall assessment and using 
all assessments, including unscheduled assessments.  
7.3.2.2 
Progression Free Survival – PSA 
PSA PFS will be estimated using the Kaplan-Meier method.  
The number and percentage of subjects with PSA progression and subjects censored will be 
summarized. The 95% Brookmeyer-Crowley CI for the proportion of subjects with PSA 
progression will also be presented. The Kaplan-Meier estimate of the median PSA PFS and 
Brookmeyer-Crowley 95% CI will be presented (Brookmeyer and Crowley 1982). 
Kaplan-Meier plots of PSA PFS will be presented.  
The analysis of PSA PFS will use all PSA assessments, including unscheduled assessments if 
applicable.  
7.3.2.3 
Progression Free Survival – Bone  
Bone PFS will be estimated using the Kaplan-Meier method.  
The number and percentage of subjects experiencing a Bone PFS even and subjects censored 
will be summarized. The 95% Brookmeyer-Crowley CI for the proportion of subjects with 
bone progression will also be presented. The Kaplan-Meier estimate of the median Bone PFS 
and Brookmeyer-Crowley 95% CI will be presented (Brookmeyer and Crowley 1982). 
Kaplan-Meier plots of Bone PFS will be presented.  
The analysis of Bone PFS will use all bone scan assessments, including unscheduled 
assessments if applicable.  
7.3.3 
Exploratory Efficacy Analyses 
7.3.3.1 
Circulating Tumor Cells 
Circulating Tumor Cells data will be listed. 
7.3.3.2 
P-eIF4E 
P-eIF4E data will be listed.  


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7.3.3.3 
Other Efficacy Analysis 
If applicable, other efficacy data will be listed.  
7.4 
Safety Analyses 
The assessment of the incidence of adverse events during the course of the study will consist 
of the surveillance and recording of adverse events (AEs), including serious adverse events 
(SAEs).  Safety will also be assessed through clinical laboratory evaluations, vital signs, 
ECGs, physical examinations, ECOG performance status, and prior and concomitant 
medication reporting.   
No formal statistical analysis of the safety data will be conducted.  Summaries will be presented 
in total for all subjects in a given population.  
Additional safety tables and/or summaries may be generated if warranted after data review.    
7.4.1 
Extent of Exposure  
Descriptive statistics will be provided for the duration of tomivosertib treatment and total 
exposure to tomivosertib. The number and percentage of subjects administered 1, 2, 3, 4, 5, 
and 6 or more treatment cycles of tomivosertib will be summarized. A cycle is defined as 28 
days. In addition, the number of subjects with a dose modification, missed dose, and dose 
interruption will be summarized including the reason for dose modification, missed dose, and 
dose interruption.  
tomivosertib exposure data will be listed.  
7.4.2 
Adverse Events 
An overview of treatment-emergent adverse events will be provided which summarizes the 
subject incidence of the following for the Safety Population: 
 Any TEAEs, 
 Drug-related TEAEs   
 CTCAE grade 3/4/5 TEAEs,  
 Drug-related CTCAE grade 3/4/5 TEAEs,  
 Any SAEs 
 Treatment-emergent SAEs (TESAEs),  
 Drug-related TESAEs,  
 TEAEs leading to dose reduction or interruption of Tomivosertib 
 TEAEs leading to discontinuation of Tomivosertib 


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 TEAEs resulting in death 
The number and percentage of subjects with TEAEs during the AE reporting period will be 
tabulated by the highest CTCAE Grade, System Organ Class (SOC), and Preferred Term (PT). 
TEAEs related to tomivosertib will be summarized in the same manner. The above summaries 
will be sorted in order of decreasing frequency.  
TEAEs will be summarized by SOC and PT. SAEs, Drug-related TEAEs, CTCAE Grade 3/4/5 
TEAEs, drug-related CTCAE Grade 3/4/5 TEAEs, TESAEs, drug-related TESAEs, AEs 
leading to dose reduction or interruption of tomivosertib, and AEs leading to discontinuation 
of tomivosertib will be summarized in the same manner. The above summaries will be sorted 
in order of decreasing frequency. A single table summary of SAEs and TESAEs may be 
presented if all SAEs meet criteria for being treatment-emergent.  
For all above summaries, subjects with multiple adverse events will be counted only once per 
SOC and preferred term.  
Advesrse events will by listed by subject. Listings will also be provided for AEs with outcome of 
death, SAEs, and AEs leading to discontinuation of tomivosertib.  
7.4.3 
Clinical Laboratory Evaluations 
Abnormal laboratory results (hematology, chemistry, and coagulation) will be graded 
according to NCI-CTCAE version 5 for applicable parameters. A shift table, presenting the 2-
way frequency tabulation for baseline and the worst post-treatment value according to the NCI-
CTCAE grade, will be provided for selected clinical laboratory tests. For select parameters, 
shift tables indicating hyper– and hypo-directionality of change may be produced.  For 
laboratory parameters with no CTCAE grading, shift tables (with categories of low, normal, 
high) from baseline to post-treatment maximum and from baseline to post-treatment minimum 
may be produced. Both scheduled and unscheduled post-treatment visits will be considered in 
tabulation of the worst post-treatment value. 
If data warrant, clinical laboratory evaluations may be summarized using descriptive statistics 
for selected laboratory parameters (hematology, chemistry, and coagulation) including 
absolute measurements and changes from baseline by scheduled time of evaluation. Changes 
from baseline by scheduled time of evaluation may include last visit on-study (End of Therapy 
Visit), maximum post-treatment value, and minimum post-treatment value. Both scheduled 
and unscheduled post-treatment visits may be considered for the summaries of the maximum 
and minimum post-treatment values 
Clinical laboratory evaluations will be listed and abnormal values will be flagged.    
7.4.4 
Vital Signs 
Vital signs data will be listed.  


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7.4.5 
Electrocardiograms 
A summary table may be produced which presents the number and percentage of subjects 
experiencing QTcF elevation or change from baseline by visit and at any time post-baseline 
for the following categories: 
 QTcF > 450 ms 
 QTcF > 480 ms 
 QTcF > 500 ms 
 Increase from baseline QTcF > 30 ms 
 Increase from baseline QTcF > 60 ms 
Shift tables from baseline to the worst post-baseline QTcF result may be presented. If 
applicable, all post-baseline ECG assessments will be considered for determination of the 
highest post-baseline value. The following categories will be used: QTcF <450 ms, 450 ms ≤ 
QTcF < 480 ms, 480 ms ≤ QTcF < 500 ms, QTcF ≥ 500 ms.  
ECG data will be listed.  
7.4.6 
Performance Status 
ECOG performance status data will be listed.  
7.4.7 
Other Safety Analyses 
Other safety assessments will be listed if applicable. 
7.5 
Pharmacokinetic Analysis 
If applicable in the future, additional details regarding the analysis of pharmacokinetic 
samples and data may be described in a standalone pharmacokinetic analysis plan.  
8 
GENERAL INFORMATION 
8.1 
Statistical Software 
The creation of analysis datasets and statistical analyses will be done using SAS® version 9.3 
or higher. The Medpace standard operating procedures (Medpace documents GL-DS-02-S3 
and GL-DS-03-S2) will be followed for the validation of all SAS programs and outputs.   
8.2 
Format of Tables, Listings, and Figures 
The format of tables, listings, and figures will be described in a stand-alone programming 
specifications document.  


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9 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSIS 
A summary of changes from the protocol-specified analysis is in Table 4 below.  
 
Table 4: Summary of Changes from Protocol-Specified Analysis 
Protocol Section 
Change 
Rationale 
Section 10.2:  
Analysis Populations 
The Efficacy Evaluable 
Population was not defined. 
Due to lack of efficacy data, the 
Safety Population will be used for 
efficacy analysis and no sensitivity 
analysis based on efficacy evaluable 
population will be planned.  
Section 10.4.2: Study 
Drug Exposure and 
Compliance 
The study drug compliance 
analysis was clarified.  
Removed number (%) of 
cycles completed (%), 
number (%) of cycles 
delayed, number of doses of 
study drug taken, cumulative 
number of days of dosing, 
cumulative dose in milligram 
analyses, number (%) of 
days study drug reported 
taken relative to the number 
of days study drug was 
expected to be taken over a 
specified period of time. 
The total exposure to 
tomivosertib, number of 
cycles intitiated, and listings 
will be used to summarize 
study drug exposure and 
compliance. 
Analysis removed due to lack of 
subjects with long-term exposure 
to study medication.  
Section 10.4.3: Prior 
and Concomitant 
Medications 
And 
Summary tables of safety 
parameters may be produced 
for prior and concomitant 
medications, laboratory, ECG, 
ECOG, and other safety 
Listings and specific summary tables 
(e.g. shift tables for specific 
laboratory parameters) were 
considered sufficient in order to 
characterize the safety assessments.  


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Section 10.4.4: 
Safety Analyses 
parameters if data warrant due 
to low number of patients 
enrolled.  
 
Section 10.4.4: Safety 
Analyses 
TEAE summaries will be 
presented for the entire 
tomivosertib treatment 
period. No summaries by 
cycle will be produced.  
TEAE tables corresponding to the 
tomivosertib treatment period 
were considered adequate 
summaries of adverse events. 
Section 10.4.5.1: 
Definition of Efficacy 
Endpoints 
The definition of Progression 
Free Survival (iPFS) was 
clarified to include clinical 
progression.  
Clinical progression added to 
capture discontinuation of study 
due to clinical progression in the 
calculation of iPFS.  
Section 10.4.5.1: 
Definition of Efficacy 
Endpoints 
Removed analysis of Overall 
Survival (OS). 
Lack of subjects with long-term 
survival follow-up data to 
adequately characterize OS. 
Section 10.4.7: 
Exploratory Analysis 
Pharmacodynamic 
assessment data will be 
listed. 
Due to low enrollment it was not 
considered feasible to perform this 
exploratory analysis.  
Section 10.4.6:  
Pharmacokinetic 
Analyses 
No PK analysis will be 
performed. If performed in the 
future it will be described in a 
separate PK analysis plan.   
Due to low enrollment no PK table 
summaries were required.   
 
 
 
 
 
 
 


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10 REFERENCES 
Brookmeyer, R., & Crowley, J. (1982). A confidence interval for the median survival 
time. Biometrics, 29-41. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008 Mar 1;26(7):1148-1159. 
Seymour, L., Bogaerts, J., Perrone, A., Ford, R., Schwartz, L. H., Mandrekar, S., ... & Hodi, 
F. S. (2017). iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. The Lancet Oncology, 18(3), e143-e152. 
Simon, R. (1989). Optimal two-stage designs for phase II clinical trials. Contemporary 
Clinical Trials, 10(1), 1-10.