Phase III study results for the drug Tesquinimod were not promising so it was a drug development decision to stop using the drug

This is a Phase I/Ib study of Radium-223 in combination with Tasquinimod for patients with bone metastases from castration-resistant prostate cancer (CRPC).

The investigators propose to determine the spectrum of tolerability of the combination of tasquinimod and radium-223 and determine a dose for a subsequent randomized phase II study (first cohort) and the proportion of men with bone-specific alkaline phosphatase response (second cohort).

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