Novel ACK1 Inhibitor (R)-9b in Patients With Prostate Cancer

ACK1/TNK2, a non-receptor tyrosine kinase contributes to prostate cancer pathophysiology.

Activated ACK1 expression is significantly correlated with the severity of disease

progression. In spite of the considerable clinical significance of pathogenic ACK1

activation in prostate [and lung & breast] cancers, no ACK1 inhibitor has been tested in

clinical trials to date. ACK1 inhibitor, (R)-9bMS, also known as (R)-9b, with IC50 of 13

nM, suppresses AR/AR-V7 levels and sensitizes Enz-resistant CRPCs.

STUDY DESIGN: This phase Ib single-center open-label The PHAROS trial, "Phase 1 First in

Human Trial to Assess Safety and Tolerability of the Novel ACK1 Inhibitor (R)-9bMS in

Patients with Prostate Cancer", will establish the safety/tolerability and recommended

phase II dosing (RP2D) for (R)-9bMS. Given the unique cancer suppressing properties of

the (R)-9bMS compound, its safety and tolerability and proposed Phase 2 dosing will be

evaluated in a first-in-human trial in CRPC patients who have stopped responding to Enz

or Abi. Post-treatment PSA levels and radiographic responses will be assessed, which will

provide preliminary assessment of the efficacy; immune responses will be evaluated, which

will provide exploratory assessment immunomodulation.

JUSTIFICATION FOR DOSE: (R)-9bMS will be administered orally twice a day, with an

interval of 12 hours between doses.

Both the 28-day rat and 28-day dog toxicity studies were conducted using the

clinically-relevant mesylate salt (MS) form of the (R)-9b drug substance.

The results of the 28-day definitive toxicity studies were used to calculate a reasonably

safe clinical starting dose for (R)-9bMS in the planned Phase 1 trial. The approach used

is consistent with guidance provided in the ICH S9 guideline and the Senderowicz 2010

publication and involves setting the starting dose at 1/10th of the STD10 in rodents. If

the nonrodent is the most appropriate species, then 1/6th of the HNSTD is considered an

appropriate starting dose.

Step #1: Identifying the rodent STD10 and nonrodent HNSTD values In the 28-day toxicity

studies conducted in rats and dogs, the STD10 and HNSTD values were identified as 60

mg/kg/day (R)-9bMS and 45 mg/kg/day (R)-9b, respectively.

- Rat STD10 = 60 mg/kg/day (R)-9bMS

- Dog HNSTD = 33.3 mg/kg/day (R)-9b [41.3 mg/kg/day (R)-9bMS]

Step #2: Converting the STD10 and HNSTD dosages from units of mg/kg/day to units of

mg/m2/day:

- Rat STD10 = 60 mg/kg/day X 6 (rat km value) = 360 mg/m2/day (R)-9bMS

- Dog HNSTD = 33.3 mg/kg/day X 20 (dog km value) = 666 mg/m2/day (R)-9b [825.8

mg/kg/day (R)-9bMS]

Step #3: The safe starting dose in humans is 1/10th of the rat STD10 or 1/6th of the dog

HNSTD:

- Rat STD10 = 360 mg/m2/day ÷ 10 = 36.0 mg/m2/day (R)-9bMS

- Dog HNSTD = 666 mg/m2/day ÷ 6 = 111 mg/m2/day (R)-9b [137.6 mg/kg/day (R)-9bMS]

Step #4: The lower of the two dosages (in mg/m2/day) is identified as the starting dose

in humans:

• 36.0 mg/m2/day < 111 mg/m2/day

For an average 60-kg individual with a body surface area of 1.62 m2, this would be a

daily dose of 58.32 mg (R)-9bMS (36.0 mg/m2/day X 1.62 m2).

One capsule containing 30 mg will be administered twice a day to patients for a total

daily dose of 60 mg for the level 1 dose.

The phase I trial adopts a Bayesian optimal interval (BOIN) design for dose

escalation/stay/de-escalation. If excessive dose limiting toxicities are observed at the

first dose level requiring dose reduction, the (R)-9bMS dose will be reduced to 30

mg/day. If no excessive toxicities are observed, the dose will escalate gradually

following the decision rules dictated to 300 mg/day in five phases. The trial expects a

maximum of 40 patients.

STRATEGIES FOR RECRUITMENT AND RETENTION Subjects seen in the Medical Oncology clinics of

the UWCCC with metastatic, castration-resistant prostate cancer, previously treated with

2nd generation AR targeted therapies, who have disease progression who meet the

eligibility criteria will be recruited. A detailed explanation of the risks and benefits

of the study will be provided, and informed consent will be obtained. Follow up will be

performed as detailed below to ensure close monitoring of safety and for evidence of side

effects.

TREATMENT PLAN Plan of Treatment: For chemistry panel, the following labs will be

performed: Albumin, ALP, amylase, ALT, AST, bicarbonate, BUN, chloride, creatinine,

glucose, calcium, LDH, lipase, magnesium, phosphorus, potassium, sodium, total bilirubin,

and total protein.

For hematology panel, the following labs will be performed: WBC count w/differential

(neutrophils, basophils, eosinophils, lymphocytes, monocytes), hematocrit, platelet

count, RBC count, hemoglobin Symptoms assessment involves review of systems for adverse

effects monitoring and toxicity grading as per NCI Common Terminology Criteria for

Adverse Events (v. 5). Screening (performed within 28 days of Day 1 unless otherwise

noted)

1. Confirm potential eligibility by history, pathology, diagnosis, and serum PSA levels

2. CT scan of chest, abdomen and pelvis; bone scan

3. Sign consent form

4. Physical examination, including vital signs, symptoms assessment, and ECOG

performance score

5. 12-lead ECG

6. Hematology and chemistry panels and serum testosterone

7. Serum PSA

8. 100 ml peripheral blood (green-top heparinized tubes) for research

9. Biopsy of metastatic site for research (only for patients treated in MTD expansion

cohort)

END OF TREATMENT (EOT)

1. Physical examination, including vital signs, weight, adverse event assessment,

concomitant medications, and ECOG performance score

2. Blood draw for hematology and chemistry panels, testosterone and PSA

3. 12-lead ECG

4. 100 mL peripheral blood (green-top heparinized tubes) for research

DOSE ESCALATION SCHEMA Level -1 30 mg PO QD; total 30 mg daily (1 capsule per day) Level

1 (Starting Dose) 30 mg PO BID; total 60 mg daily (2 capsules per day) Level 2 60 mg PO

BID; total 120 mg daily (4 capsules per day) Level 3 90 mg PO BID; total 180 mg daily (6

capsules per day) Level 4 120 mg PO BID; total 240 mg daily (8 capsules per day) Level 5

150 mg PO BID; total 300 mg daily (10 capsules per day)

DEFINITION OF MTD, DLT and DOSE ESCALATION CRITERIA The maximum tolerated dose (MTD) is

defined as the dose level immediately below the dose level at which two patients of a

cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle.

Dose escalations will proceed until the MTD has been reached.

Dose Limiting Toxicities (DLTs)

- DLTs are defined as any (R)-9bMS related (TRAE) toxicity that are ≥ Grade 3

occurring within the 28 days post (R)-9bMS treatment (starting with first day of

dosing), with the following caveats:

- Any ≥ Grade 3 hematologic toxicities EXCEPT:

- Grade 3 neutropenia lasting < 7 days

- Grade 3 thrombocytopenia without bleeding or requiring platelet transfusion

- Any ≥ Grade 3 Non-hematologic toxicities EXCEPT:

- Grade 3 nausea, vomiting and/or diarrhea lasting < 72 hours

- Grade 3 fatigue lasting < 7 days

- Any non-hematologic Grade 3 clinical laboratory AE that is asymptomatic and

returns to ≤ Grade 2 within 72 hours * Asymptomatic Grade 3 electrolyte

abnormalities, symptomatic Grade 3 abnormalities that persist >72 hours despite

appropriate replacement therapy will be considered a DLT

- Additionally, the following events will be considered DLTs if they occur during the

first cycle:

- Any Grade 5 toxicity

- Any death not clearly due to the underlying disease or extraneous causes

- Any event that meets Hy's law criteria

- Delay in Cycle 2 due to toxicity by > 14 days

DURATION OF THERAPY

In the absence of treatment delays due to adverse events, treatment may continue for up

to 1 year or until one of the following criteria applies:

- Documented and confirmed disease progression

- Death

- Adverse event(s) that, in the judgment of the investigator, may cause severe or

permanent harm or which rule out continuation of study drug

- Specific conditions described in the dose modifications section

- If the subject does not recover from his toxicities to tolerable grade ≤ 2 within 6

weeks, the subject will have study treatment discontinued

- Inability to tolerate the minimum protocol-specified dose of study treatment

- Participation in another clinical study using an investigational agent,

investigational medical device, or other intervention

- General or specific changes in the patient's condition render the patient unable to

receive further treatment in the judgment of the investigator

- Serious noncompliance with the study protocol

- Patient withdraws consent

- Request by regulatory agencies for termination of an individual subject or all

subjects under the protocol

DURATION OF FOLLOW-UP Patients will have a safety follow-up visit or a review of the

medical record at 12 months to assess disease and survival status.

DATA AND SAFETY MONITORING PLAN

The entities providing oversight of safety and compliance with the protocol require

reporting, as outlined below. Adverse events (AE) include the following:

1. An exacerbation, or an unexpected increase in frequency or intensity of a

pre-existing condition, including intermittent or episodic conditions.

2. Significant or unexpected worsening or exacerbation of the condition/indication

under investigation.

3. A suspected drug interaction.

4. An intercurrent illness.

5. Any clinically significant laboratory abnormality.

Serious adverse events (SAE) are any events occurring that result in any of the following

outcomes:

1. Subject death

2. Life-threatening adverse event

3. Inpatient hospitalization or prolongation of existing hospitalization

4. Persistent or significant disability/incapacity

5. Congenital anomaly or birth defect

A life-threatening event is defined as any adverse event that places the subject, in the

view of the investigator, at immediate risk of death from the reaction.

- Is another important medical event

- Is a new cancer

- Is associated with an overdose.

SEVERITY RATING/GRADING SCALE: Adverse events are classified by organ system and graded

by severity according to the current NIH Common Terminology Criteria V. 5. The defined

grades use the following general guidelines:

- 0 No adverse event or within normal limits

- 1 Mild adverse event

- 2 Moderate adverse event

- 3 Severe adverse event

- 4 Life-threatening or disabling adverse event

- 5 Fatal adverse event

All adverse events will be recorded from time of treatment initiation through 30 days

after the final dose of study treatment, as well as any time after these 30 days for

events that are believed to be at least possibly related to study treatment.

B. Disease Oriented Team Meetings UWCCC site: This study undergoes review of subject

safety at regularly scheduled Disease Oriented Team (DOT) meetings where the following

are discussed as applicable: number of subjects enrolled, subject treatments given, dose

holds/modifications, significant toxicities, response to treatment, and the subjects'

overall status. These discussions are documented in the DOT meeting minutes.

C. UWCCC Data and Safety Monitoring Committee (DSMC) Study Progress Review and Oversight

The review of Protocol Summary Reports (PSRs) enables the UWCCC DSMC to assess whether

the study should continue, continue with modifications, be suspended, or be closed.

Following their review, the UWCCC DSMC will notify the sponsor-investigator of their

recommendation and the authority for continuing, modifying, suspending, or closing the

protocol is the responsibility of the applicable sponsor-investigator, Principal

Investigator, IRB, FDA or other regulatory authority associated with the protocol.

Based on the risk level of this study, as determined by the UWCCC Protocol Review and

Monitoring Committee, PSRs must be submitted to the UWCCC DSMC by the UWCCC site on a

quarterly basis.

The UWCCC site is responsible for ensuring participating sites enter data used to

populate the PSRs in a timely manner into the UWCCC instance of OnCore. These data

include: accrual information, Serious Adverse Events (SAEs), response to treatment,

events reportable to IRB (e.g., non-compliance, unanticipated problems).

1. UWCCC DSMC Review of Auditing and/or Monitoring Reports Reports created through the

auditing and/or monitoring activities at all sites are submitted in real-time by the

UWCCC site to the UWCCC DSMC. Summary data and/or query reports are submitted in

lieu of detailed reports. Following the review of these reports, the committee may

issue a request for corrective and/or preventive action(s), protocol suspension, or

for-cause audit(s).

2. UWCCC DSMC Review of Non-compliance, Unanticipated Problems, and Other IRB

Reportable Events UWCCC site: Reports of non-compliance, unanticipated problems, and

other IRB reportable events are submitted to the IRB of record for the study and to

the UWCCC DSMC, via an email to DSMC@carbone.wisc.edu, simultaneously.

3. Real-time UWCCC DSMC Review of Serious Adverse Events (SAEs) The UWCCC DSMC Chair,

or designee, reviews all SAEs occurring on the study, regardless of site, to

determine if immediate action is required.

UWCCC site: The Principal Investigator (PI), or designee, notifies the following

individuals/entities of SAEs as applicable:

- Other investigators involved with the study at the UWCCC

- IRB of record for the study conducted at the UWCCC, per the IRB's reporting

requirements

- UWCCC DSMC

- Medical Monitor: Dr. Saurabh Rajguru

- Sponsor (TechnoGenesys): Dr. Gerald Andriole o Email: jerry@technogenesys.com

D. Serious Adverse Event Reporting Serious Adverse Events Requiring 24-Hour Reporting

UWCCC site: All Serious Adverse Events must be reported within 24 hours to the UWCCC DSMC

Chair via an email to saenotify@uwcarbone.wisc.edu within one business day. The OnCore

SAE Details Report must be submitted along with other report materials as appropriate

(FDA Medwatch Form #3500, UWCCC routing form, de-identified supporting documentation

available at that time of initial reporting).

E. Sponsor Responsibilities for SAE Review

The sponsor (i.e., TechnoGenesys IND holder) will have the responsibilities of the study

sponsor in accordance with FDA 21 CFR 312.32. In this capacity, the sponsor reviews all

reports of serious adverse events occurring on the study and makes a documented

determination of 1) suspectedness (i.e., whether there is a reasonable possibility that

the drug caused the AE); and 2) unexpectedness (the event is not listed in the

Investigator's Brochure or is not listed at the specificity or severity that has been

observed) in the context of this study. SAE with suspected causality to study drug and

deemed unexpected are reported as IND Safety Reports by the sponsor, or designee, to the

following within 15 calendar days unless otherwise designated below:

- FDA

- All participating investigators on the study, and the external global sponsor (if

applicable).

- Other oversight committees (NIH OSP) All fatal or life-threatening SAE that are

unexpected and have suspected causality to the study drug will be reported by the

Sponsor (TechnoGenesys), or designee, to the following within 7 calendar days: Dr.

Gerald Andriole; Email: jerry@technogenesys.com