PI3Kbeta Inhibitor AZD8186 and Docetaxel in Treating Patients Advanced Solid Tumors With PTEN or PIK3CB Mutations That Are Metastatic or Cannot Be Removed by Surgery
Condition: Advanced Breast Carcinoma; Advanced Malignant Solid Neoplasm; Advanced Prostate Carcinoma; Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IIIA Breast Cancer AJCC v8; Anatomic Stage IIIB Breast Cancer AJCC v8; Anatomic Stage IIIC Breast Cancer AJCC v8; Anatomic Stage IV Breast Cancer AJCC v8; Castration-Resistant Prostate Carcinoma; Metastatic Breast Carcinoma; Metastatic Malignant Solid Neoplasm; Metastatic Prostate Carcinoma; Prognostic Stage III Breast Cancer AJCC v8; Prognostic Stage IIIA Breast Cancer AJCC v8; Prognostic Stage IIIB Breast Cancer AJCC v8; Prognostic Stage IIIC Breast Cancer AJCC v8; Prognostic Stage IV Breast Cancer AJCC v8; Stage III Prostate Cancer AJCC v8; Stage IIIA Prostate Cancer AJCC v8; Stage IIIB Prostate Cancer AJCC v8; Stage IIIC Prostate Cancer AJCC v8; Stage IV Prostate Cancer AJCC v8; Stage IVA Prostate Cancer AJCC v8; Stage IVB Prostate Cancer AJCC v8; Triple-Negative Breast Carcinoma; Unresectable Solid Neoplasm
MeSH terms: Carcinoma; Breast Neoplasms; Prostatic Neoplasms; Neoplasms
Intervention: Docetaxel; Laboratory Biomarker Analysis; Pharmacological Study; PI3Kbeta Inhibitor AZD8186
Intervention description: Given IV; Correlative studies; Correlative studies; Given PO
Intervention MeSH terms: Docetaxel
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 23.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase I trial studies the side effects and best dose of PI3Kbeta inhibitor AZD8186 when
      given together with docetaxel in treating patients with solid tumors with PTEN or PIK3CB
      mutations that have spread to other places in the body (metastatic) or cannot be removed by
      surgery. PI3Kbeta inhibitor AZD8186 may stop the growth of tumor cells by blocking some of
      the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in
      different ways to stop the growth of tumor cells, either by killing the cells, by stopping
      them from dividing, or by stopping them from spreading. Giving PI3Kbeta inhibitor AZD8186 and
      docetaxel may work better in treating patients with solid tumors.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically confirmed malignancy that is metastatic or
             unresectable and for which standard curative or palliative measures do not exist or
             are no longer effective

          -  Patients must be able to swallow and retain oral medications and be without
             gastrointestinal illnesses that would preclude absorption of AZD8186

          -  Unlimited prior therapies allowed

          -  Docetaxel appropriate

               -  Patients who have not received prior docetaxel (or other taxane therapy) in the
                  advanced setting are eligible for all cohorts

               -  Patients who have previously received docetaxel (or other taxane therapy) in the
                  advanced setting are eligible for the dose escalation cohort only, if anticipated
                  to have maintained taxane sensitivity and in the opinion of the investigator
                  would still benefit from further docetaxel therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Hemoglobin >= 8 g/L

          -  Platelets >= 100,000/mcL

          -  Total bilirubin within normal institutional limits

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 1.5 x institutional upper limit of normal

          -  Creatinine within normal institutional limits OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

          -  PTEN or PIK3CB mutated advanced solid tumor

               -  PTEN loss of function mutation or PIK3CB gain of function mutation identified by
                  local Clinical Laboratory Improvement Act (CLIA) certified next generation
                  sequencing (NGS)

               -  Breast cancers patients enrolled on this study must have either:

                    -  Estrogen receptor positive and HER2 negative breast cancer

                    -  Triple negative breast cancer

          -  Adequate archival tissue (metastatic tissue sample is preferable but primary tumor
             tissue will be acceptable) or willing to undergo pre-treatment biopsy (for central
             confirmation of molecular alteration and PTEN immunohistochemical assessment) if
             adequate archival tissue is unavailable

          -  The effects of AZD8186 on the developing human fetus are unknown; for this reason,
             women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation; should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately; men treated or enrolled on this protocol must also
             agree to use adequate contraception prior to the study, for the duration of study
             participation, and 4 months after completion of AZD8186 administration

          -  Ability to understand and the willingness to sign a written informed consent document

          -  DOSE ESCALATION COHORT: Prior receipt of docetaxel is permitted

          -  DOSE ESCALATION COHORT: Measurable disease is not required for enrollment

          -  PHARMACODYNAMIC EXPANSION COHORT: Prior receipt of docetaxel is not permitted

          -  PHARMACODYNAMIC EXPANSION COHORT: Patients must have measurable disease, defined as at
             least one lesion that can be accurately measured in at least one dimension (longest
             diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >=
             20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT)
             scan, magnetic resonance imaging (MRI), or calipers by clinical exam

          -  PHARMACODYNAMIC EXPANSION COHORT: Consent to allow mandatory paired (pre- and on-
             treatment) fresh tissue biopsies if deemed safe to do so for quantitation of Akt
             pathway signaling proteins

          -  DISEASE SPECIFIC EXPANSION COHORTS: Prior receipt of docetaxel is not permitted

          -  DISEASE SPECIFIC EXPANSION COHORTS: Patients (excepting the prostate cancer patients)
             must have measurable disease, defined as at least one lesion that can be accurately
             measured in at least one dimension (longest diameter to be recorded for non-nodal
             lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as
             >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam

          -  DISEASE SPECIFIC EXPANSION COHORTS: Breast cancers patients enrolled on this study
             must have:

               -  Metastatic or advanced (incurable and unresectable) HER2 negative breast cancer
                  regardless of estrogen receptor status (both hormone receptor positive and triple
                  negative patients are eligible)

               -  Received hormonal therapy, as appropriate based on their hormone receptor status;
                  hormone receptor positive patients who have not received endocrine therapy for
                  recurrent/metastatic disease are eligible, permitted their physician feels they
                  are not appropriate for first line endocrine therapy, for example for high risk
                  visceral metastatic disease

          -  DISEASE SPECIFIC EXPANSION COHORTS: Prostate cancers patients enrolled on this study
             (applies to all prostate cancer patients treated on parts 1, 2, and 3) must have:

               -  Metastatic or advanced (incurable and unresectable) castration resistant
                  metastatic cancer

               -  Received at least one additional line of anti-androgen therapy with abiraterone
                  or enzalutamide

               -  Measurable disease is not required for enrollment

        Exclusion Criteria:

          -  HER2 positive breast cancer

          -  Prior treatment with PI3K/AKT inhibitors

          -  Any known concurrent RAF or PIK3CA mutation

          -  Patients who have had chemotherapy, radiotherapy, immunotherapy or anticancer agents
             within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of the first dose of study
             treatment, except hormonal therapy with luteinizing hormone-releasing hormone (LHRH)
             analogues for medical castration in patients with prostate cancer and breast cancer,
             which are permitted

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1)

          -  Patients who are receiving any other investigational agents

          -  Patients with known, untreated or unstable 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; patients with treated brain metastases are eligible if the
             metastases have been radiographically and clinically stable for at least one month; if
             on steroids for this indication, the patient must be on a stable dose for at least one
             month

          -  History of clinically significant allergic reactions attributed to compounds of
             similar chemical or biologic composition to AZD8186 or docetaxel or to docetaxel
             itself

          -  Patients receiving any medications or substances that are strong inhibitors and/or
             strong or moderate inducers of CYP3A4 are ineligible; because the lists of these
             agents are constantly changing, it is important to regularly consult a
             frequently-updated medical reference; as part of the enrollment/informed consent
             procedures, the patient will be counseled on the risk of interactions with other
             agents, and what to do if new medications need to be prescribed or if the patient is
             considering a new over-the-counter medicine or herbal product

          -  Existing bleeding or condition associated with increased risk of bleeding

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, uncontrolled hypertension, symptomatic congestive heart failure, unstable
             angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
             would limit compliance with study requirements

          -  Pregnant women are excluded from this study because AZD8186 is a PI3K inhibitor with
             the potential for teratogenic or abortifacient effects; because there is an unknown
             but potential risk for adverse events in nursing infants secondary to treatment of the
             mother with AZD8186, breastfeeding should be discontinued if the mother is treated
             with AZD8186; these potential risks may also apply to other agents used in this study

          -  Human immunodeficiency virus (HIV)-patients positive for human immunodeficiency virus
             (HIV) are NOT excluded from this study, but HIV-positive patients must have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART) that does not
                  include strong inhibitors and strong or moderate inducers of CYP3A4

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  polymerase chain reaction (PCR)-based test