Clinical Trials /

Ibrutinib as Neoadjuvant Therapy in Localized Prostate Cancer

NCT02643667

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib as Neoadjuvant Therapy in Localized Prostate Cancer
  • Official Title: A Phase 2 Study of Ibrutinib as Neoadjuvant Therapy in Patients With Localized Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: 201808057
  • NCT ID: NCT02643667

Conditions

  • Prostate Cancer

Interventions

DrugSynonymsArms
IbrutinibPhase I: Ibrutinib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Phase I: IbrutinibExperimentalIbrutinib: will be given by mouth daily Blood samples for PSA and for immune assays will be collected at baseline, before RP, and after RP Radical prostatectomy will be performed at least 7 days but not more than 12 days following the last scheduled dose of ibrutinib
  • Ibrutinib
Phase II: IbrutinibExperimentalIbrutinib: will be given by mouth daily Blood samples for PSA and for immune assays will be collected at baseline, before RP, and after RP Radical prostatectomy will be performed at least 7 days but not more than 12 days following the last scheduled dose of ibrutinib
  • Ibrutinib

Eligibility Criteria

        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.

          -  Moderate or severe hepatic impairment defined as Child-Pugh Class B or C.

          -  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.

          -  Major surgery within 4 weeks of the 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicities (Phase 1)
Time Frame:Completion of enrollment of Phase I portion of patients
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Dose-dependent change in B cell infiltration (Phase 1)
Time Frame:Completion of follow-up (approximately 10 weeks after start of treatment)
Safety Issue:
Description:Immunohistochemistry (ICH)
Measure:Dose-dependent change in T cell infiltration (Phase 1)
Time Frame:Completion of follow-up (approximately 10 weeks after start of treatment)
Safety Issue:
Description:Immunohistochemistry (ICH)
Measure:Dose-dependent change in circulating B cells (Phase 1)
Time Frame:Completion of follow-up (approximately 10 weeks after start of treatment)
Safety Issue:
Description:Flow cytometry
Measure:Dose-dependent change in circulating T cells (Phase 1)
Time Frame:Completion of follow-up (approximately 10 weeks after start of treatment)
Safety Issue:
Description:Flow cytometry
Measure:Change in frequency of circulating B cells (Phase 2)
Time Frame:Completion of follow-up (approximately 10 weeks after start of treatment)
Safety Issue:
Description:Flow cytometry
Measure:Change in frequency of circulating T cells (Phase 2)
Time Frame:Completion of follow-up (approximately 10 weeks after start of treatment)
Safety Issue:
Description:Flow cytometry
Measure:Cytotoxic effect (Phase 2)
Time Frame:Completion of follow-up (approximately 10 weeks after start of treatment)
Safety Issue:
Description:Laboratory evaluations (>/= 50% PSA decline)
Measure:Treatment response
Time Frame:Completion of follow-up (approximately 10 weeks after start of treatment)
Safety Issue:
Description:Pathologic down-staging and/or pathologic T0

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

Trial Keywords

  • Radical prostatectomy (RP)

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