Navitoclax and Abiraterone Acetate With or Without Hydroxychloroquine in Treating Patients With Progressive Metastatic Castrate Refractory Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Abiraterone; ABT-263; Hydroxychloroquine
Intervention description: ARM A(Abiraterone with ABT-263) and ARM B(Abiraterone with both ABT-263 and Hydroxychloroquine); ARM A(Abiraterone with ABT-263) and ARM B(Abiraterone with both ABT-263 and Hydroxychloroquine); ARM B(Abiraterone with both ABT-263 and Hydroxychloroquine)
Intervention MeSH terms: Hydroxychloroquine; Navitoclax
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: prostate cancer; hormone-resistant prostate cancer; recurrent prostate cancer; stage IV prostate cancer

Summary:

      The purpose of this study is to assess the effect of combining abiraterone with medicines
      that may block some of the ways that cells become resistant to abiraterone. The investigators
      hope that these combinations of medicines will result in prostrate cancer cells dying.

      This study will see if overcoming diseases resistance to abiraterone will restore sensitivity
      to androgen deprivation therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have had evidence of disease progression while receiving primary
             androgen suppression therapy by orchiectomy or other primary hormonal therapy and
             abiraterone (Specifically, patients can have received multiple prior additional
             androgen axis targeting agents including enzalutamide, and prior chemotherapy, but
             must have had progression (as defined in 5.1.2) while receiving abiraterone either
             currently or in the past). Patients currently on abiraterone may continue with the
             start of the study drug(s).

          -  Patients must have evidence of disease progression during current or prior therapy
             with abiraterone with either:

               1. Biochemical progression as defined as rising PSA from a nadir or baseline
                  (whichever was lowest) confirmed on a second determination at least 1 week later
                  that must be higher than the first and must have reached ≥2ng/ml (if no other
                  evidence of progression); or

               2. New Metastases on bone scan (at least 2); or

               3. Progression of measurable disease on CT scan by RECIST criteria

          -  Age >18 years and an estimated life expectancy of at least 6 months.

          -  Treatment with at least 2 months of abiraterone prior to progression

          -  ECOG performance status ≤ 2. (See Appendix A)

          -  Patients must be ≥ 4 weeks since completing their prior therapy (including surgery,
             radiation therapy or investigational therapy (including targeted small molecule
             agents)). All previous clinically significant treatment-related toxicities have
             resolved to ≤ Grade 1. Patients must be ≥ 4 weeks since prior therapy with an
             anti-androgen

          -  Adequate renal function (serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥50
             ml/min)

          -  Total bilirubin must be within 1.5 X the normal institutional limits. If total
             bilirubin is outside the normal institutional limits, assess direct bilirubin. The
             direct bilirubin must be within normal parameters. Transaminases (SGOT and/or SGPT)
             must be less than 1.5X ULN concomitant with alkaline phosphatase less than 5X the ULN.

          -  An ANC >1500/μl, hemoglobin > 8.5 g/dl, and platelet count >100,000/mm3 are required.

          -  Serum testosterone (total) less than 25 ng/ml at time of enrollment.

          -  Bisphosphonates/RANK-ligand inhibitor allowed if started prior to study treatment

          -  Patient must consent to using effective contraception while on treatment and for 3
             months thereafter

          -  Subject must voluntarily sign and date an informed consent, approved by an Independent
             Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of
             any screening or study-specific procedures

        Exclusion Criteria:

          -  Known infection with HIV or subject has tested positive for HIV (due to potential
             drug-drug interactions between anti-retroviral inhibitors and ABT-263, as well as
             anticipated ABT-263 mechanism based lymphopenia that may potentially increase the risk
             of opportunistic infections and potential drug-drug interactions with certain anti
             infective agents). Patients without prior HIV testing will not be required to be
             tested.

          -  Second primary malignancy except most situ carcinoma (e.g. adequately treated
             non-melanomatous carcinoma of the skin) or other malignancy treated at least 5 years
             previously with no evidence of recurrence.

          -  Patients with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          -  Subject exhibits evidence of other clinically significant uncontrolled condition(s)
             including, but not limited to:

               -  active systemic fungal infection;

               -  diagnosis of fever and neutropenia within 1 week prior to study drug
                  administration

          -  Patients must discontinue all herbal supplements at a minimum of one week prior to
             initiation of therapy (such information will be collected on each patient

          -  Requirement for routine use of hematopoietic growth factors (including granulocyte
             colony stimulating factor, granulocyte macrophage colony stimulating factor, or
             interleukin-11) or platelet transfusions to maintain absolute neutrophil counts or
             platelets counts above the required thresholds for study entry.

          -  Patient has an underlying, predisposing condition of bleeding or currently exhibits
             signs of bleeding. The subject has a recent history of non-chemotherapy induced
             thrombocytopenic associated bleeding within 1 year prior to the first dose of study
             drug.

          -  History or symptoms of cardiovascular disease (NYHA Class 2, 3, or 4; see Appendix B,
             New York Heart Association Criteria) within the last 6 months, particularly coronary
             artery disease, arrhythmias, or conduction defects with risk of cardiovascular
             instability, uncontrolled hypertension, clinically significant pericardial effusion,
             or congestive heart failure.

          -  Hypersensitivity to 4-aminoquinoline compounds, including hydroxychloroquine sulfate,
             chloroquine phosphate and amodiaquine.

          -  Prior history of treatment with ABT-263

          -  Known G-6PDH deficiency

          -  Retinal or visual field changes from prior 4-aminoquinoline compound use such as
             hydroxychloroquine sulfate, chloroquine phosphate and amodiaquine.

          -  Patients presenting with untreated cord compression are not eligible (patients with
             prior treatment and stability will be eligible)

          -  Concurrent use of other investigational agent

          -  Subject has undergone an allogeneic stem cell transplant

          -  Subject has active peptic ulcer disease or other hemorrhagic esophagitis/gastritis

          -  Subject has a significant history of cardiovascular disease (e.g., MI, thrombotic or
             thromboembolic event in the last 6 months), renal, neurologic, psychiatric,
             endocrinologic, metabolic, immunologic, or hepatic disease that in the opinion of the
             Investigator would adversely affect his/her participating in this study. Subject has
             received a biologic agent for anti-neoplastic intent within 30 days prior to the first
             dose of study drug.

          -  Subject is currently receiving or requires anticoagulation therapy (e.g., warfarin at
             any dose) or any drugs (e.g., aspirin, clopidogrel, etc) or herbal supplements that
             affect platelet function, with the exception of low molecular weight heparin or
             heparin that are used to maintain the patency of a catheter.

          -  Subject has received aspirin or warfarin within 7 days prior to the first dose of
             study drug.

          -  Subject has consumed grapefruit or grapefruit products within 3 days prior to the
             first dose of study drug.

          -  Received potent CYP3A inhibitors (e.g., ketoconazole) or inducers (substrates of
             CYP2D6) within 7 days prior to the first dose of study drug.

          -  Subject has received rifampin within 4 days prior to first dose of ABT-263