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

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of
PI3Kbeta inhibitor AZD8186 (AZD8186) when administered in combination with docetaxel in
patients with PTEN or PIK3CB mutated advanced solid tumors.

II. To assess the safety and tolerability of AZD8186 when administered in combination with
docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To assess the objective response rate (ORR)
of AZD8186 when administered in combination with docetaxel in patients with PTEN or PIK3CB
mutated advanced solid tumors.

III. To assess the clinical benefit rate at 24 weeks of AZD8186 when administered in
combination with docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors.

IV. To investigate a drug-drug interaction between docetaxel and AZD8186 and correlate drug
exposure with pharmacodynamics response.

EXPLORATORY OBJECTIVES:

I. Examine the pattern of co-mutated genes in PTEN or PIK3CB mutated tumors and their
association with treatment response or resistance.

II. Describe possible mechanisms of acquired resistance to PI3Kbeta inhibition. III.
Evaluation of protein expression of the PTEN gene and its association with treatment response
or resistance.

IV. Examine isoform-specific AKT inhibition and other downstream target modulation from
PI3Kbeta inhibition with AZD8186.

OUTLINE: This is a dose-escalation study of PI3Kbeta inhibitor AZD8186.

Patients receive docetaxel intravenously (IV) over 1 hour on day 1 and PI3Kbeta inhibitor
AZD8186 orally (PO) twice daily (BID) for 5 days each week. Courses repeat every 21 days in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3
months.

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

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits (patients with confirmed Gilbert's
syndrome with a total bilirubin =< 2.0 x upper limit of normal [ULN], may be included
in this study)

- 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 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

- 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