Pacritinib for Biochemical Relapse After Definitive Treatment for Prostate Cancer
Pacritinib for Biochemical Relapse After Definitive Treatment for Prostate Cancer
This is a single-arm, open-label study using pacritinib for patients with histologically
 confirmed prostate adenocarcinoma, status post definitive treatment and biochemical
 recurrence.
This phase 2, single-arm, open-label study using pacritinib will treat patients with
 histologically confirmed prostate adenocarcinoma, status post definitive treatment and
 biochemical recurrence.

 The primary objective of this study is to determine the effect of pacritinib on the time to
 prostate-specific antigen (PSA) progression in patients with biochemical relapse of prostate
 cancer (defined as the length of time that a given subject will be alive and free from PSA
 progression per Prostate Cancer Working Group 3 (PCWG3) guidelines.
Inclusion Criteria:

 1. Patients aged ≥ 18 years.

 2. Histologically or cytologically confirmed prostate adenocarcinoma.

 3. Prior radical prostatectomy or definitive radiation.

 4. Biochemically recurrent prostate cancer with PSA doubling time ≤ 12 months at the time
 of study entry (calculated per Memorial Sloan Kettering Cancer Center (MSKCC) prostate
 nomogram: https://www.mskcc.org/nomograms/prostate/psa_doubling_time). Calculation of
 PSA doubling time should include the use of all available PSA values obtained within
 the past 12 months prior to randomization, with a minimum of three values separated by
 at least two weeks apart. The PSA values used to calculate the PSA doubling time must
 all be ≥ 0.1 ng/mL and should be measured in the same laboratory whenever feasible.

 5. Prior adjuvant or salvage radiation or not a candidate for radiation based upon
 clinical assessment of disease characteristics and patient comorbidities. (N/A for
 patients who underwent definitive radiation therapy).

 6. Screening PSA > 0.5 ng/mL.

 7. No definitive evidence of metastases on screening computerized tomography scan (CT) or
 magnetic resonance imaging (MRI) of abdomen/pelvis and radionuclide whole-body bone
 scan per the judgment of the investigator. Abdominal and/or pelvic lymph nodes
 measuring 1.5 cm or less in short axis diameter are allowed. Lesions identified on
 other imaging modalities (e.g. prostate specific membrane antigen (PSMA) or choline
 positron emission tomography (PET)) that are not visualized on CT and/or MRI or
 radionuclide bone scan are allowed. Equivocal lesions on bone scan should be followed
 up with additional imaging as clinically indicated.

 8. Screening serum testosterone > 150 ng/dL.

 9. Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 or 1 or Karnofsky
 Performance Status ≥ 70.

 10. No prior Janus Kinase 2 (JAK2) inhibitor treatment.

 11. Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree
 to one of the following:

 • Practice effective barrier contraception during the entire study period and through
 60 calendar days after the last dose of study agent

 12. Ability to understand a written informed consent document, and the willingness to sign
 it.

 13. Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated
 acquisition (MUGA) scan.

 14. Willing to provide blood and tissue for research analysis. (encouraged but not
 necessary for inclusion in trial).

 15. Adequate organ function as defined by the following laboratory values at screening:

 -  Serum aspartate transaminase (AST), serum glutamic oxaloacetic transaminase
 (SGOT) and serum alanine transaminase (ALT), serum glutamic pyruvic transaminase
 (SGPT) < 2.5 x upper limit of normal (ULN).

 -  Total serum bilirubin ≤1.5 x ULN. In subjects with Gilbert's syndrome, if total
 bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct
 bilirubin is ≤1.5 × ULN, the subject may be eligible).

 -  Serum potassium ≥ 3.5 mmol/L. Supplementation and re-screening is allowed.

 -  Estimated glomerular filtration rate (GFR) > 45 ml/min using Cockroft-Gault
 equation.

 -  Platelets ≥ 100,000/mL independent of transfusion and/or growth factors within
 three months prior to randomization.

 -  Hemoglobin ≥ 9.0 g/dL independent of transfusion and/or growth factors within
 three months prior to randomization.

 -  Absolute neutrophil count ≥500/µL.

 -  Serum albumin ≥ 3.0 g/dL.

 -  Adequate coagulation defined by prothrombin time (PT) / international normalized
 ratio (INR) and partial thromboplastin time (PTT) ≤ 1x.5 ULN.

 Exclusion Criteria:

 1. Previously treated with pacritinib.

 2. Prior systemic treatment with androgen deprivation therapy and/or first-generation
 anti-androgen (e.g. bicalutamide, nilutamide, flutamide) for biochemically recurrent
 prostate cancer. Prior androgen deprivation therapy (ADT) and/or first-generation
 anti-androgen in the (neo)adjuvant, definitive and/or salvage setting in conjunction
 with radiation or surgery is allowed provided last effective dose of ADT and/or
 first-generation anti-androgen is > 9 months prior to the date of randomization and
 the total duration of prior therapy is ≤ 36 months.

 3. Prior treatment with 17α-hydroxy / 17,20-lyase (CYP17) inhibitor (e.g., ketoconazole,
 abiraterone acetate, galeterone) or next-generation androgen receptor antagonist
 including apalutamide or enzalutamide.

 4. Prior chemotherapy for prostate cancer except if administered in the neoadjuvant or
 adjuvant setting and last dose <= 6 months from randomization.

 5. Use of 5-alpha reductase inhibitor within 42 days prior to randomization.

 6. Use of investigational agents within 28 days prior to randomization.

 7. Use of other prohibited medications within seven days prior to Cycle 1 Day 1 on study
 (see Appendix 3 and 4 for list of prohibited medications).

 8. Systemic treatment with a strong Cytochrome P450 3A4 (CYP3A4) inhibitor or a strong
 cytochromes P450 (CYP450) inducer within 14 days prior to treatment Day 1 (Appendix 3
 and Appendix 4, respectively)

 9. Prior bilateral orchiectomy.

 10. Uncontrolled hypertension.

 11. Baseline severe hepatic impairment (Child-Pugh Class B & C).

 12. An intercurrent illness that is not controlled, such as active infection, psychiatric
 illness/social situations that would limit compliance with study requirements.

 13. Any chronic medical condition requiring a higher dose of corticosteroid than an
 equivalent of 10 mg prednisone/prednisolone per day.

 14. Significant recent bleeding history, as defined as National Cancer Institute (NCI)
 Common Terminology Criteria for Adverse Events (CTCAE) grade≥2 within three months
 prior to treatment Day 1, unless precipitated by an inciting event (e.g., surgery,
 trauma, or injury)

 15. Systemic treatment with medications that increase the risk of bleeding, including
 anticoagulants (warfarin, direct oral anticoagulant, etc.), antiplatelet agents
 (except for aspirin dosages of ≤ 100mg/day), vascular endothelial growth factor
 (anti-VEGF) agents, and daily use of COX-1 inhibiting nonsteroidal anti-inflammatory
 agents (NSAIDs) within 14 days prior to treatment Day 1.

 16. Systemic treatment with medications that can prolong the time from the start of the Q
 wave to the end of the T wave (QT interval) within 14 days prior to treatment Day 1.
 Shorter washout periods may be permitted with the approval of the principal
 incestigator, provided that the washout period is at least five half-lives of the drug
 prior to treatment Day 1.

 17. Any history of CTCAE grade ≥2 cardiac conditions within six months before treatment
 Day 1. Patients with asymptomatic grade 2 non-dysrhythmia cardiovascular conditions
 may be considered for inclusion, with the approval of the PI, if stable and unlikely
 to affect patient safety.

 18. QT corrected by the Fridericia method (QTcF) prolongation >450 ms or other factors
 that increase the risk for QT interval prolongation (e.g., heart failure, hypokalemia
 [defined as serum potassium <3.0 mEq/L that is persistent and refractory to
 correction]), or history of long QT interval syndrome.

 19. New York Heart Association Class II, III, or IV congestive heart failure (Appendix 7).

 20. Any active gastrointestinal (GI) or metabolic condition that could interfere with
 absorption of oral medication.

 21. Active or uncontrolled inflammatory or chronic functional bowel disorder such as
 Crohn's disease, inflammatory bowel disease, chronic diarrhea, or chronic
 constipation.

 22. Other malignancy within three years prior to treatment Day 1, other than curatively
 treated basal cell or squamous cell skin or corneal cancer; curatively treated
 carcinoma in situ of the cervix; or in situ breast carcinoma after complete surgical
 resection.

 23. Uncontrolled intercurrent illness, including, but not limited to, ongoing active
 infection, psychiatric illness, or social situation that, in the judgment of the
 treating physician, would limit compliance with study requirements.

 24. Known seropositivity for human immunodeficiency virus.

 25. Known active hepatitis A, B, or C virus infection.