A Study of Radium-223 in Combination With Tasquinimod in Bone-only Metastatic Castration-Resistant Prostate Cancer

This is a study of Radium-223 in combination with Tasquinimod. The target population is
patients with bone metastases from castration-resistant prostate cancer intended for
treatment with radium-223.

After baseline assessment, all subjects will receive six cycles of Radium-223 separated by
an interval of 28 days. Radium-223 will be administered per FDA-approved dosing (six IV
injections at a dose of 50kBq/kg of body weight, administered every 4 weeks). The treatment
maintenance dose of tasquinimod will be a maximum of 1 mg of tasquinimod taken once daily
with water (~200 mL). The initial target dose of tasquinimod is 0.5mg/day. All subjects will
be followed up for 12 months after start of study treatment.

The investigators propose a phase I/Ib trial of the addition of tasquinimod to FDA-approved
doses of radium-223 in men with symptomatic bone-only metastatic CRPC. The investigators
anticipate that given their distinct mechanisms of action and non-overlapping toxicity
profiles that additive or synergistic toxicity would be minimal. The investigators
hypothesize that adding tasquinimod to radium therapy may result in improved measures of
efficacy including reduction in total alkaline phosphatase, time to first skeletal-related
event and PSA and radiographic progression-free survival.

In the Phase I portion of dose-escalation scheme, the dose escalation will follow a 3+3
design with intra-patient dose-escalation from 0.25mg/day of tasquinimod to a goal dose of
either 0.25mg (dose-level -1), 0.5mg (dose-level 1), or 1.0mg/day (dose-level 2) based on
individual tolerability.

Upon identifying a recommended Phase II combination dose-level of Radium-223 and
tasquinimod, the investigators will move to the Phase Ib portion and open an expanded cohort
of up to 35 additional patients to achieve a total of 38 patients treated at the recommended
phase II dose-level (including those from the dose-escalation phase).

Inclusion Criteria:

1. Age at least 18 years at the time of signing the ICF

2. Histologically or cytologically confirmed adenocarcinoma of the prostate

3. Two or more bone metastases (hot spots) confirmed by bone scintigraphy within 8 weeks
prior to study entry

4. Pain at baseline judged by the investigator to be related to bone metastases

5. Known castration-resistant disease, defined according to PCWG2 criteria as:

- Castrate serum testosterone level: ≤50 ng/dL (≤1.7 nmol/L)

- Subjects who have failed initial hormonal therapy, either by orchiectomy or by
using a GnRH agonist in combination with an anti-androgen, must first progress
through antiandrogen withdrawal prior to being eligible. The minimum timeframe
to document failure of anti-androgen withdrawal will be four weeks

- Progressive disease based on PSA and/or radiographic criteria:Serum PSA
progression defined as two consecutive increases in PSA over a previous
reference value within 6 months of first study treatment, each measurement at
least one week apart. Serum PSA at screening ≥ 2 ng/mL, Or Radiographic disease
progression based on documented bone lesions by the appearance of two or more
new lesions by bone scintigraphy

6. Karnofsky Performance Status (KPS): ≥70% within 14 days before start of study
treatment (ECOG ≤1)

7. Life expectancy: at least 6 months

8. Laboratory requirements:

- White Blood Cell (WBC) count ≥ 3 x 109/L

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelet count ≥ 100 x109/L

- Hemoglobin ≥10.0 g/dL

- Total bilirubin ≤ 1.5 x ULN

- AST and ALT ≤ 3 x ULN

- Creatinine ≤ 1.5 x ULN

9. If sexually active with partner of childbearing potential, patient will agree to use
adequate contraceptive methods (barrier contraceptive with spermicide or vasectomy)
while on study drug. The adequate contraceptive method should be continued for 6
months after the last dose of radium-223 or 14 days after the last dose of
tasquinimod, whichever comes later.

10. No evidence (within 5 years) of prior malignancies (except successfully treated basal
cell or squamous cell carcinoma of the skin).

11. Able to swallow and retain oral medication.

12. The subject is willing and able to comply with the protocol, and agrees to return to
the hospital for follow-up visits and examination

13. The subject has been fully informed about the study and has signed the informed
consent form and, where appropriate, HIPAA authorization for release of personal
health information

Exclusion Criteria:

1. Has received an investigational therapeutic drug within the last 4 weeks prior to
start of study treatment, or is scheduled to receive one during the treatment period.

2. Has received external radiotherapy within the last 4 weeks prior to start of study
treatment.

3. Previous therapy with antiandrogens within 4 weeks (within 6 weeks for bicalutamide
eg, Casodex®).

4. Concurrent use of other anticancer agents or treatments, with the following
exceptions:

- Ongoing treatment with LHRH agonists or antagonists, denosumab (Prolia) or
bisphosphonate (eg, zoledronic acid) is allowed. Ongoing treatment should be
kept at a stable schedule; however, if medically required, a change of dose,
compound, or both is allowed.

5. Any treatment modalities involving major surgery within 4 weeks prior to the start of
study treatment.

6. Has received prior hemibody external radiotherapy.

7. Has received systemic radiotherapy (e.g. samarium, strontium etc.) for the treatment
of bone metastases.

8. Has received blood transfusion or erythropoietin (EPO) within the last 4 weeks prior
to start of study treatment.

9. Has received prior treatment with Radium-223.

10. Malignant lymphadenopathy exceeding 3 cm in short-axis diameter.

11. Symptomatic nodal disease, i.e. scrotal, penile or leg edema.

12. Visceral metastases from CRPC (>2 lung and/or liver metastases [size ≥2cm]), as
assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior
to start of study treatment.

13. Uncontrolled loco-regional disease.

14. Other primary tumor (other than CRPC) including hematological malignancy present
within the last 5 years (except non-melanoma skin cancer or low-grade superficial
bladder cancer).

15. Ongoing treatment with warfarin unless the international normalized ratio is well
controlled and below 4. Treatment with other anticoagulants is allowed.

16. Maintenance treatment with corticosteroids corresponding to a prednisolone or
prednisone dose above 10 mg/day. The dose must have been stable for at least 5 days.

17. Systemic exposure to ketoconazole or other strong CYP3A4 isozyme inhibitors or
inducers (Appendix A) within 14 days prior to the start of study treatment. Systemic
exposure to amiodarone is not allowed within 1 year prior to the start of study
treatment.

18. Ongoing treatment with sensitive CYP1A2 substrate or CYP1A2 substrate with narrow
therapeutic range (Appendix A) at the start of study treatment.

19. Ongoing treatment with CYP3A4 substrate with narrow therapeutic range (Appendix A) at
the start of study treatment.

20. Has imminent or established spinal cord compression based on clinical findings and/or
MRI.

21. Any other serious illness or medical condition that would, in the opinion of the
investigator, make this protocol unreasonably hazardous, including, but not limited
to:

- Any uncontrolled infection

- Cardiac failure NYHA (New York Heart Association) III or IV

- Crohn's disease or ulcerative colitis

- Bone marrow dysplasia

- Known allergy to any of the compounds under investigation

- Unmanageable fecal incontinence