Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment

Background:

- Enzalutamide is established as first-line hormonal therapy in patients with metastatic
castration resistant prostate cancer (mCRPC). However, it is increasingly recognized
that acquired resistance to therapy (e.g. AR overexpression, AR-V7) could limit the
durability of response to therapy

- Upregulation of HIF-1Alpha in hypoxic tumor cells provides a mechanism of acquired
resistance to current hormonal therapies and chemotherapies. Acquired resistance
increases angiogenesis and metastasis, leading to disease progression

- Targeting the hypoxia driven tumor microenvironment (e.g. down-regulation of HIF-1Alpha)
in addition to the androgen receptor (e.g. enzalutamide) has synergistic activity
against prostate cancer cell line models (e.g. LNCaP, 22Rv1).

- CRLX101 is a nanoparticle drug conjugate composed of 20(S)-camptothecin (a potent and
highly selective topoisomerase I inhibitor with anti-HIF-1Alpha properties) conjugated
to a linear, cyclodextrin-polyethylene glycol-based polymer

- CRLX101 has been to shown to be safe, tolerable, and efficacious in numerous Phase II
clinical investigations in a variety of tumor subtypes.

- Preclinical and clinical studies have shown CRLX101 significantly down-regulates
HIF-1alpha, impacting tumor-driven angiogenesis.

- The treatment combination of CRLX101 and enzalutamide provides a reasonable approach to
re-sensitizing prostate cancer cells to hormonal therapy via synergistic antitumor
activity and inhibition of acquired resistance

Objectives:

-Primary Objective: To evaluate the anti-tumor activity of CRLX101 at the recommended phase
II dose (RP2D) in combination with enzalutamide with respect to treatment response, defined
as greater than or equal to 50% PSA decline or stable disease on imaging following 5 months
of treatment.

Eligibility:

- Patients must have progressive mCRPC per Prostate Cancer Working Group 3(PCWG3)

- Patients must be at least 18 years of age and able to give informed consent

- ECOG Performance Status less than or equal to 2

- Evaluable metastatic disease on bone scan or measurable disease on CT Scan per PCWG3
and/or RECIST

- Patients must have had disease progression while receiving prior enzalutamide treatment

Design:

- The study will be conducted using an optimal two stage Phase II design (8 patients,
expandable to 21 patients total) aimed to determine the percentage of patients with a
PSA decline of greater than 50% or stable disease at 5 months.

- The first 3 to 6 patients enrolled on study will follow a lead-in dosing scheme to
confirm the safety of the combination (CRLX101 12 mg/m(2) every 2 weeks for the first
two cycles, followed by CRLX101 15 mg/m(2) every 2 weeks at the start of cycle 3, with
enzalutamide 160 mg administered once daily starting on cycle 1 day 2) prior to
initiation of the optimal two stage study design.

- For patients enrolled on study following the lead-in, the confirmed tolerable dose of
CRLX101 will be administered via IV infusion every 2 weeks. Enzalutamide 160 mg will be
administered orally once daily beginning on cycle 1 day 2.

- Blood and urine will be collected at multiple time points for PK and PD analyses.

- Tumor assessments will be made using 99Tc bone scintography and/or CT scan (chest,
abdomen, and pelvis) at baseline, prior to Cycle 3 and every 3 cycles thereafter.

- The accrual ceiling for the study is set at 30 patients.

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed prostate cancer confirmed
by either the Laboratory of Pathology at the NIH Clinical Center or Walter Reed
National Military Medical Center at Bethesda prior to starting this study. If no
pathological specimen is available, patients may enroll with a pathologist s report
showing a histological diagnosis of prostate cancer and clinical course consistent
with the disease.

- Patients must have progressive mCRPC. There must be radiographic evidence of disease
progression or biochemically (rising PSA levels on successive measurements) recurring
disease despite adequate testosterone suppression.

- Progression must be evidenced and documented by any of the following parameters:

- PSA progression defined by a minimum of two rising PSA levels with an interval of
greater than or equal to 1 week between each determination

- Appearance of one or more new lesions consistent with prostate cancer on bone
scan

- New or growing lesions on CT scan

- Patients must have metastatic disease, per RECIST 1.1(64).

- Patients must have discontinued enzalutamide at least 28 days prior to enrollment.

- Patients must have received treatment with prior enzalutamide for two or more cycles
and must have had evidence of disease progression while on enzalutamide.

- Patients who have received antiandrogens such as flutamide, bicalutamide, or
nilutamide for >6 months immediately before enrollment on this study must be off
treatment for 4 weeks (6 weeks for bicalutamide) and demonstrate a continued rise in
PSA. Patients on antiandrogens for <6 months must be off medication for 2 weeks.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of enzalutamide and CRLX101 in patients <18 years of
age and prostate cancer is not common in children <18 years of age, children are
excluded from this study.

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin within normal institutional limits; for patients with Gilbert s
syndrome, total bilirubin less than or equal to 3.0 mg/dL

- hemoglobin greater than or equal to 9g/dL

- serum albumin greater than or equal to 2.8 g/dL

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal (<5 times institutional ULN for liver metastases)

- creatinine within 1.5 times normal institutional limits

OR

--creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
creatinine levels above institutional normal.

- Patients must have castrate levels of testosterone (<50 ng/dL [1.74 nmol/L]).

- Patients must have undergone bilateral surgical castration or must continue on GnRH
agonists/antagonists for the duration of the study.

- Patients on 5-alpha reductase inhibitors such as finasteride or dutasteride must stop
medication at least 28 days prior to study entry.

- The effects of enzalutamide and CRLX101 on the developing human fetus are unknown. For
this reason and because androgen receptor antagonists and topoisomerase I inhibitors
as well as other therapeutic agents used in this trial are known to be teratogenic,
all study subjects must agree to use a condom during the study treatment period and
for 120 days following the last dose of study drug. Should a woman become pregnant or
suspect she is pregnant while her partner is participating in this study, she should
inform her treating physician immediately.

- ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to
60%).

- Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents. A minimum washout period
of 28 days is required prior to the initiation of on study treatment.

- Patients who have been treated with prior secondary hormonal manipulations with
proposed investigational rationale for having efficacy against AR-V7 splice variants.

This includes but is not limited to EPI-002 and AZD5312. (Note: patients previously treated
with abiraterone, orteronel (TAK-700), apalutamide (ARN-509), galeterone, or VT-464 will be
eligible for this study. Patients who have received prior chemotherapy will also be
eligible for this study).

- 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.

- Patients with history of seizure as an adult including febrile seizure or any
condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous
malformation, head trauma with loss of consciousness requiring hospitalization). Also
current or prior treatment with anti-epileptic medications for the treatment of
seizures. Transient ischemic attack within 12 months prior to study enrollment will
not be permitted.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to enzalutamide, CRLX101, or other agents used in study.

- Patients with a history within the last 3 years of another invasive malignancy
(localized non-melanoma skin and bladder cancers are allowed).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, uncontrolled hypertension (SBP>170/DBP>105), or psychiatric illness/social
situations within 6 months that would limit compliance with study requirements.

- Patients who have received palliative radiotherapy within 2 weeks of study entry and
have not recovered to Grade 1 or baseline from associated toxicities. Note: Patients
may receive palliative radiation once enrolled on study. The subject has not recovered
to baseline or CTCAE less than or equal to Grade 1 from toxicity due to all prior
therapies, including surgery, except alopecia and other non-clinically significant
AEs.

- Patients who are unable to swallow tablets or have a gastrointestinal disease that
could hinder the absorption of enzalutamide

- The use of any herbal products that may lower PSA levels (e.g. saw palmetto).

- Patients with microscopic hematuria (defined as >100 RBCs on urinalysis) or worsening
urinary symptoms within 7 days prior to the initiation of study treatment.

- Known HIV-positive patients on antiretroviral therapy are ineligible because of
potential pharmacokinetic interations with study drugs. However, patients with
long-standing (>5 years) HIV on antiretroviral therapy >1 month (undetectable HIV
viral load and CD4 count > 150 cells/micro L) may be eligible if the Principal
Investigator or designee determines no anticipated clinically significant drug-drug

interactions.

INCLUSION OF MINORITIES AND WOMEN:

-Men of all races and ethnic groups are eligible for this trial. Women are excluded as
prostate cancer does not exist in this population.