Prostate Cancer
Conditions
Keywords
Radical prostatectomy (RP)
Brief summary
30-40% of patients who undergo radical prostatetecomy (RP) with curative intent for their localized prostate cancer experience relapse of their disease. Thus, improved therapeutic approaches are needed in this patient population. Enhancing the patient's anti-tumor immune response prior to surgery may improve long-term outcomes following RP
Interventions
DRUGIbrutinib
-Ibrutinib will be supplied by Pharmacyclics Inc.
PROCEDURERadical prostatectomy
-Standard of care
Sponsors
Pharmacyclics LLC.
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years of age or older * ECOG performance status 0 or 1 * Histologically documented adenocarcinoma of the prostate * Patients must be suitable for and willing to undergo a radical prostatectomy at the completion of study therapy. * Adequate bone marrow function, defined as: * WBC \>2,500 cells/mm3 * ANC \>1,500 cells/mm3 * Hemoglobin \>9 mg/dL * Platelet count \>100,000 cells/mm3 * Adequate renal function, defined as serum creatinine \<2 mg/dL or CrCl \>30 mL/min * Adequate liver function, defined as: * AST and ALT \<2.5x institutional ULN * Serum bilirubin \<1.5x institutional ULN * Adequate coagulation function, defined as normal PT/INR and PTT * Ability to understand and willingness to sign a written informed consent document * Available evaluable archival tumor tissue for correlative studies including assessment of immune infiltration and Btk expression is required. If archival tissue is unavailable, patients must be willing to undergo repeat prostate biopsy. Tissue is considered sufficient for correlative endpoint analyses if they are obtained from at least 2 prostate cores and consist of at least 15 unstained slides from the largest tumor volume and/or highest Gleason score. The availability of archival tissue or consent for repeat prostate biopsy is required for study eligibility; determination of tissue sufficiency is not required for study eligibility. * The effects of ibrutinib on the developing human fetus is unknown. Men treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of the study participation, and for 3 months after completion of treatment.
Exclusion criteria
* Patients with neuroendocrine or small cell features are not eligible. * Any evidence of metastatic disease. Pre-operative staging will be undertaken per urologic standard of care. * Any prior use of hormonal therapy, including: * GNRH agonists or GNRH antagonists (e.g., leuprorelin, degarelix) * Antiandrogens (e.g., bicalutamide, flutamide, nilutamide) * Novel androgen-directed therapies (e.g., abiraterone, enzalutamide) * Any estrogen containing compounds * 5-alpha reductase inhibitors (e.g., finasteride, dutasteride) * PC-SPES or PC-x products. Other herbal therapies or supplements will be considered by the Principle Investigator on a case by case basis based on their potential for hormonal or anti-cancer therapies. * Chemotherapy ≤ 21 days prior to first administration of study treatment and/or monoclonal antibody ≤ 6 weeks prior to first administration of study treatment * Prior radiation therapy for prostate cancer * Prior exposure to BTK inhibitors * Prior investigational therapy for prostate cancer * Patients may not receive any other concurrent investigational agents while on study. * Use of systemic steroid therapy within 28 days of study screening. Patients on inhaled or topical steroids are eligible. * Concurrent systemic immunosuppressive therapy within 21 days of the first dose of study drug. * Major surgery requiring the use of general anesthetic within 4 weeks of study enrollment * HIV, active hepatitis B (HBV) or active hepatitis C (HCV) * Patients with past HBV infection or resolved HBV infection, defined as the presence of hepatitis B core antibody (HBc Ab) and absence of hepatitis B surface antigen (HBsAg) are eligible. HBV DNA must be obtained in these patients prior to day 1 of ibrutinib therapy, but detection of HBV DNA in these patients will not exclude study participation. * Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. * Inability to swallow capsules or presence of malabsorption syndromes, disease significantly affecting gastrointestinal function, history of resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete small obstruction. * Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Function Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to screening. * Uncontrolled concurrent illness, or any underlying medical condition, which in the Principal Investigator's opinion will make the administration of ibrutinib hazardous or obscure the interpretation of adverse events. * Recent infection requiring systemic treatment that was completed within 14 days prior to the first dose of study drug * Concurrent active malignancy other than non-melanoma skin cancers. Patients are considered to be free of active malignancy if they have completed curative therapy and have a \<30% risk of relapse. * History of congenital bleeding diathesis. * Known bleeding disorders (e.g. von Willebrand's disease or hemophilia). * Concomitant use of anticoagulants including warfarin, other Vitamin K antagonists, and enoxaparin. * Subjects who received a strong or moderate cytochrome P450 (CYP) 3A4 inhibitor within 7 days prior to the first dose of ibrutinib or patients who require treatment with a strong or moderate cytochrome P450 (CYP) 3A inhibitor. * Vaccination with live, attenuated vaccines within 4 weeks of first dose of study drug. * Patients on anti-platelet agents including clopidogrel and glycoprotein IIb/IIIa inhibitors. Aspirin is allowed, but should be held before surgery according to standard practices. * Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child-Pugh classification * Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk. * Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to CTCAE v 4.03 grade 0 or 1 or to the levels dictated in the eligibility criteria with the exception of alopecia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (Phase I and Safety Run-In) | Completion of DLT follow-up (2 weeks for Phase I portion and 28 days for Safety Run-In) | * CTCAE v.4.0 * DLTs will be defined as any of the following that are attributable to ibrutinib. * Any grade 4 toxicity, including hematologic toxicities with the exception of lymphocytosis. Lymphocytosis, in the absence of clinical symptoms, is excluded from DLT, as this may be considered an on-target pharmacodynamics effect of BTK inhibition. * Any grade 3 toxicity. * Any recurrence of the same grade 3 toxicity. * Any delay of RP due to study-drug related toxicity. * Any complications of RP (e.g., bleeding, delayed wound healing) deemed to be related to study drug. |
| Percentage of Participants With Positive Responses - CD20+ B Cells, IL-10+ B Cells, CD3+ T Cells, CD8+ Cytotoxic T Cells, Effector CD4+FOXP3- T Cells, and CD4+FOX3+ T Regulatory Cells | Pre-treatment and at time of RP (approximately 10 weeks after start of treatment) | In pre-treatment biopsy, RP tissue, and reference RP tissue quantitated by immunohistochemistry (IHC). Patients will be considered to have a positive response if there is \>2 fold decrease from pre-treatment to post-treatment, or considered to have a negative response if there is \<2 fold decrease. The percentage of participants who have positive responses are represented in the outcome measure data. |
| Mean B Cell Fold Change of CD20+ B Cells | At RP (approximately 10 weeks after start of treatment) | Participants will be considered to have a positive response if there is \>2 fold decrease (0.5 or less B cell fold change) or considered to have a negative response if there is \<2 fold decrease. Descriptive statistics will be used to describe pre-treatment biopsy immune infiltration, post-treatment RP immune infiltration, and immune infiltration of reference RP tissue. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Positive Responses - CD19+ B Cells, CD25^highCD27^highCD86^High B Regulatory Cells, and CD3+, CD8+, CD4+FOXP3- and CD4+FOXP3+ T Cells Induced by Neoadjuvant Ibrutinib in Patients by Flow Cytometry | Pre-treatment to RP (approximately 10 weeks after start of treatment) | Patients will be considered to have a positive response if there is \>2 fold decrease from pre-treatment to post-treatment, or considered to have a negative response if there is \<2 fold decrease. The percentage of partcipants who have positive responses are represented in the outcome measure data. |
| Number of Participants Who Had a 50% or Greater Decline in PSA | At baseline and approximately day 29 | — |
| Number of Participants With a Treatment Response (Safety Lead-In and Phase II Only) | Completion of follow-up (approximately 10 weeks after start of treatment) | Pathologic down-staging and/or pathologic T0 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Ibrutinib * Ibrutinib 840 mg by mouth once daily for 2 weeks.
* Radical prostatectomy will be performed at least 7 days but not more than 12 days following the last scheduled dose of ibrutinib. | 3 |
| Safety Run-In and Phase II: Ibrutinib * Ibrutinib 840 mg by mouth once daily for 4 weeks.
* Radical prostatectomy will be performed at least 7 days but not more than 12 days following the last scheduled dose of ibrutinib | 24 |
| Total | 27 |
Baseline characteristics
| Characteristic | Phase I: Ibrutinib | Total | Safety Run-In and Phase II: Ibrutinib |
|---|---|---|---|
| Age, Continuous | 61 years | 61 years | 62.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 27 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 27 Participants | 24 Participants |
| Region of Enrollment United States | 3 participants | 27 participants | 24 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 27 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 24 |
| other Total, other adverse events | 3 / 3 | 24 / 24 |
| serious Total, serious adverse events | 0 / 3 | 5 / 24 |
Outcome results
Primary
Mean B Cell Fold Change of CD20+ B Cells
Participants will be considered to have a positive response if there is \>2 fold decrease (0.5 or less B cell fold change) or considered to have a negative response if there is \<2 fold decrease. Descriptive statistics will be used to describe pre-treatment biopsy immune infiltration, post-treatment RP immune infiltration, and immune infiltration of reference RP tissue.
Time frame: At RP (approximately 10 weeks after start of treatment)
Population: Only those in the Safety Run-In and Phase II portion were evaluable for this outcome measure. Additional participants in the Safety Run-In were not analyzed for this outcome measure due to either missing sample or too few cells in the sample to analyze. The investigators were unable to analyze matched/paired samples due to sample processing issues with the enrolled patients diagnostic biopsies (not enough evaluable tissue or unable to obtain biopsy tissue from outside medical center).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Safety Run-In and Phase II: Ibrutinib | Mean B Cell Fold Change of CD20+ B Cells | 0.9 B cell fold change |
Primary
Number of Participants With Dose Limiting Toxicities (Phase I and Safety Run-In)
* CTCAE v.4.0 * DLTs will be defined as any of the following that are attributable to ibrutinib. * Any grade 4 toxicity, including hematologic toxicities with the exception of lymphocytosis. Lymphocytosis, in the absence of clinical symptoms, is excluded from DLT, as this may be considered an on-target pharmacodynamics effect of BTK inhibition. * Any grade 3 toxicity. * Any recurrence of the same grade 3 toxicity. * Any delay of RP due to study-drug related toxicity. * Any complications of RP (e.g., bleeding, delayed wound healing) deemed to be related to study drug.
Time frame: Completion of DLT follow-up (2 weeks for Phase I portion and 28 days for Safety Run-In)
Population: Only participants enrolled in the Phase I portion and the 6 participants in the Safety Run-In portion of the Phase II portion are evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Ibrutinib | Number of Participants With Dose Limiting Toxicities (Phase I and Safety Run-In) | 0 Participants |
| Safety Run-In and Phase II: Ibrutinib | Number of Participants With Dose Limiting Toxicities (Phase I and Safety Run-In) | 0 Participants |
Primary
Percentage of Participants With Positive Responses - CD20+ B Cells, IL-10+ B Cells, CD3+ T Cells, CD8+ Cytotoxic T Cells, Effector CD4+FOXP3- T Cells, and CD4+FOX3+ T Regulatory Cells
In pre-treatment biopsy, RP tissue, and reference RP tissue quantitated by immunohistochemistry (IHC). Patients will be considered to have a positive response if there is \>2 fold decrease from pre-treatment to post-treatment, or considered to have a negative response if there is \<2 fold decrease. The percentage of participants who have positive responses are represented in the outcome measure data.
Time frame: Pre-treatment and at time of RP (approximately 10 weeks after start of treatment)
Population: Only those in the Safety Run-In and Phase II portion were evaluable for this outcome measure. Additional participants in the Safety Run-In were not analyzed for this outcome measure due to either missing sample or too few cells in the sample to analyze. The investigators were unable to analyze matched/paired samples due to sample processing issues with the enrolled patients diagnostic biopsies (not enough evaluable tissue or unable to obtain biopsy tissue from outside medical center).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD20+ B Cells, IL-10+ B Cells, CD3+ T Cells, CD8+ Cytotoxic T Cells, Effector CD4+FOXP3- T Cells, and CD4+FOX3+ T Regulatory Cells | CD20+ B cells | 53.8 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD20+ B Cells, IL-10+ B Cells, CD3+ T Cells, CD8+ Cytotoxic T Cells, Effector CD4+FOXP3- T Cells, and CD4+FOX3+ T Regulatory Cells | IL10+ B cells | 40 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD20+ B Cells, IL-10+ B Cells, CD3+ T Cells, CD8+ Cytotoxic T Cells, Effector CD4+FOXP3- T Cells, and CD4+FOX3+ T Regulatory Cells | CD3+ T cells | 7.1 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD20+ B Cells, IL-10+ B Cells, CD3+ T Cells, CD8+ Cytotoxic T Cells, Effector CD4+FOXP3- T Cells, and CD4+FOX3+ T Regulatory Cells | CD8+ T cells | 0 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD20+ B Cells, IL-10+ B Cells, CD3+ T Cells, CD8+ Cytotoxic T Cells, Effector CD4+FOXP3- T Cells, and CD4+FOX3+ T Regulatory Cells | CD4+ Foxp3- T cells | 0 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD20+ B Cells, IL-10+ B Cells, CD3+ T Cells, CD8+ Cytotoxic T Cells, Effector CD4+FOXP3- T Cells, and CD4+FOX3+ T Regulatory Cells | CD4+ Foxp3+ T cells | 13.3 percentage of participants |
Secondary
Number of Participants Who Had a 50% or Greater Decline in PSA
Time frame: At baseline and approximately day 29
Population: If participants did not have the day 29 PSA drawn then they are not included in the overall number of participants analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Ibrutinib | Number of Participants Who Had a 50% or Greater Decline in PSA | 0 Participants |
| Safety Run-In and Phase II: Ibrutinib | Number of Participants Who Had a 50% or Greater Decline in PSA | 0 Participants |
Secondary
Number of Participants With a Treatment Response (Safety Lead-In and Phase II Only)
Pathologic down-staging and/or pathologic T0
Time frame: Completion of follow-up (approximately 10 weeks after start of treatment)
Population: Only participants in the Safety Lead-In and Phase II portion of the study who had a radical RP are evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Run-In and Phase II: Ibrutinib | Number of Participants With a Treatment Response (Safety Lead-In and Phase II Only) | 7 Participants |
Secondary
Percentage of Participants With Positive Responses - CD19+ B Cells, CD25^highCD27^highCD86^High B Regulatory Cells, and CD3+, CD8+, CD4+FOXP3- and CD4+FOXP3+ T Cells Induced by Neoadjuvant Ibrutinib in Patients by Flow Cytometry
Patients will be considered to have a positive response if there is \>2 fold decrease from pre-treatment to post-treatment, or considered to have a negative response if there is \<2 fold decrease. The percentage of partcipants who have positive responses are represented in the outcome measure data.
Time frame: Pre-treatment to RP (approximately 10 weeks after start of treatment)
Population: Only those in the Safety Run-In and Phase II portion were evaluable for this outcome measure. Additional participants in the Safety Run-In were not analyzed for this outcome measure due to either missing sample or too few cells in the sample to analyze.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD19+ B Cells, CD25^highCD27^highCD86^High B Regulatory Cells, and CD3+, CD8+, CD4+FOXP3- and CD4+FOXP3+ T Cells Induced by Neoadjuvant Ibrutinib in Patients by Flow Cytometry | CD19+ B cells | 38.1 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD19+ B Cells, CD25^highCD27^highCD86^High B Regulatory Cells, and CD3+, CD8+, CD4+FOXP3- and CD4+FOXP3+ T Cells Induced by Neoadjuvant Ibrutinib in Patients by Flow Cytometry | CD25+CD27+CD86+ regulatory B cells | 35 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD19+ B Cells, CD25^highCD27^highCD86^High B Regulatory Cells, and CD3+, CD8+, CD4+FOXP3- and CD4+FOXP3+ T Cells Induced by Neoadjuvant Ibrutinib in Patients by Flow Cytometry | CD3+ T cells | 14.3 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD19+ B Cells, CD25^highCD27^highCD86^High B Regulatory Cells, and CD3+, CD8+, CD4+FOXP3- and CD4+FOXP3+ T Cells Induced by Neoadjuvant Ibrutinib in Patients by Flow Cytometry | CD8+ T cells | 9.5 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD19+ B Cells, CD25^highCD27^highCD86^High B Regulatory Cells, and CD3+, CD8+, CD4+FOXP3- and CD4+FOXP3+ T Cells Induced by Neoadjuvant Ibrutinib in Patients by Flow Cytometry | CD4+ Foxp3- T cells | 14.3 percentage of participants |
| Safety Run-In and Phase II: Ibrutinib | Percentage of Participants With Positive Responses - CD19+ B Cells, CD25^highCD27^highCD86^High B Regulatory Cells, and CD3+, CD8+, CD4+FOXP3- and CD4+FOXP3+ T Cells Induced by Neoadjuvant Ibrutinib in Patients by Flow Cytometry | CD4+ Foxp3+ T cells | 14.3 percentage of participants |