Trial of CRLX101, a Nanoparticle Camptothecin With Olaparib in People With Relapsed/Refractory Small Cell Lung Cancer

Background:

- Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis.

- Although highly responsive to chemotherapy initially, SCLC relapses quickly and becomes
refractory to treatment within a few months.

- Urothelial Carcinoma (UC) of the Bladder is the fourth most common malignancy in men and
the ninth most common in women.

- Prostate cancer is the most common cancer among men in the United States. While prostate
cancer is initially responsive to androgen deprivation therapy (ADT), the median
duration of sensitivity is 24-36 months. Moreover, patients develop resistance to
current treatment options.

- The use of PARP inhibitors in combination with chemotherapy builds upon pre-clinical
data in lung cancer and other cancers supporting the notion that PARP inhibitors
potentiate the effect of DNA damaging therapies.

- Despite their highly synergistic activity in preclinical models, human studies combining
PARP inhibitors and camptothecins have not translated into clinical benefit due to
enhanced toxicity with the combination.

- One approach to improve ability to combine camptothecins with agents that sensitize
their activity like PARP inhibitors is to use alternative formulations that minimize
toxicity to the normal tissues.

- CRLX101 is a nanoparticle drug conjugate composed of 20 (S)-camptothecin (a potent and
highly selective topoisomerase I inhibitor) conjugated to a linear,
cyclodextrinpolyethylene glycol-based polymer.

- Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or
suspected deleterious germline BRCA mutated advanced ovarian cancer who have been
treated with three or more prior lines of chemotherapy. Olaparib has an established
safety profile and it is under investigation in a number of different cancers.

Objectives:

- Phase I: To determine the MTD/ recommended Phase 2 dose (RP2D) of CRLX101 in combination
with olaparib in patients with refractory cancers

- Phase II: To determine the antitumor activity of olaparib plus CRLX101 with respect to
progression free survival at 16 weeks in SCLC patients with resistant or sensitive
relapse

- Expansion Cohorts: To determine overall response rate of CRLX101 plus olaparib in

patients with mCRPC and urothelial carcinoma

Eligibility:

Phase I:

- Male or female adult patients (Bullet)18 years of age

- Histologically or cytologically confirmed, advanced solid tumor that is refractory to

standard therapy and/or for whom no further standard therapy is available

-ECOG Performance Status of 0, 1 or 2

Phase II:

- Male or female patients greater than or equal to 18 years old

- Have a pathologically (histology or cytology) confirmed diagnosis of SCLC

- Disease progression on or after at least one platinum-based standard chemotherapy

regimen and/or an immune-checkpoint inhibitor for either limited or extensive stage

disease.

- Have measurable disease per RECIST 1.1

- ECOG performance status of 0, 1 or 2

Phase II Expansion Cohorts:

-Have a pathologically (histology or cytology) confirmed diagnosis of urothelial

carcinoma or metastatic, progressive, castrate resistant prostate cancer (mCRPC)

-Disease progression on or after at least one platinum-based standard chemotherapy

regimen and/or an immune-checkpoint inhibitor (except prostate cohort)

- Have measurable disease per RECIST 1.1 (except prostate cohort)

- Prior treatment with enzalutamide and/or abiraterone (prostate cancer cohort only)

- Patients must have castrate levels of testosterone (<50 ng/dl [1.74 nmol/l]) (Prostate

cohort only)

Design:

- Patients meeting eligibility criteria will receive CRLX101 (IV Q 2weeks) plus olaparib
(PO BID days 3-13 and days 17-26 administered in 28 day cycles, until disease
progression or development of intolerable side effects. The MTD of the combination will
be used in Phase II.

- Patients in Phase II will receive, the RP2D at DL4R CRLX101 12mg/m2 and olaparib 250mg
BID.

- Blood, tumor and hair samples will be collected at multiple time points for PK, PD
analyses. Hair sample collection is optional. Tumor biopsies are optional for SCLC and
UC patients and mandatory for mCRPC patients (only baseline biopsy is mandatory).

- Toxicity will be graded according to CTCAE version 4.0.

- Tumor assessments will be made using CT scans (chest, abdomen and pelvis) at baseline
and after every 2 cycles (3 cycles for mCRPC) according to RECIST version 1.1.

- After discontinuation of study treatment, follow-up for survival will be carried out
every 3 months.

- The maximum number of patients on the phase I portion of the trial is 30, the SCLC
cohort in phase II may accrue up to 27 evaluable patients, urothelial carcinoma
expansion cohort may accrue up to 34 patients and mCRPC may accrue up to 25 patients.
Thus, the maximum number of evaluable patients who may enroll on this trial is 116. In
order to allow for a small number of in-evaluable patients, the accrual ceiling will be
set at 123.

- It is anticipated that approximately 1 to 2 patients per month may enroll onto this
trial; the trial is expect to complete accrual in 6-8 years.

- INCLUSION CRITERIA:

Phase I:

- Patients must have advanced solid tumor that is resistant or refractory to standard
therapy.

- A minimum of 2 weeks will be required from any prior therapy, including chemotherapy,
immunotherapy and/or radiation. In addition, recovery to Grade less than or equal to 1
from all reversible toxicities related to prior therapy is required at study entry.

- Patients do not need to have measurable disease to enroll on phase I.

- Age greater than or equal 18 years.

- ECOG performance status less than or equal to 2.

- Patients with treated brain metastases (surgery, whole or stereotactic brain
radiation) are allowed provided the lesions have been stable for at least 2 weeks and
the patient is off steroids or is on a stable dose of steroids. Patients with brain
metastases should not require use of enzyme-inducing antiepileptic drugs (e.g.,
carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and
during study. Use of newer antiepileptics that do not produce enzyme induction
drug-drug interactions (DDIs) is allowed.

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

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

- absolute neutrophil count >1,500/mcL without growth factor support

- platelets greater than or equal 100,000/mcL without growth factor support

- hemoglobin greater than or equal 9 g/dL and no blood transfusion within 4 weeks
OR greater than 10 g/dL and no blood transfusion within 2 weeks.

- total bilirubin less than or equal 1.5 x ULN (unless Gilbert s Disease)

- AST(SGOT)/ALT(SGPT) less than or equal 2.5 X institutional upper limit of normal
(less than or wqual to 5X ULN if liver mets)

- creatinine less than ULN OR

- creatinine clearance greater than or equal 51 mL/min (calculated using the
Cockroft- Gault formula) for patients with creatinine levels above institutional
normal.

- The effects of CRLX101 and olaparib on the developing human fetus are unknown. For
this reason and because these agents as well as other therapeutic agents used in this
trial are known to be teratogenic, 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, for the duration of study participation and for 120
days (both male and female) following last dose of study drug. 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. Fertile females of
childbearing potential are defined as women physically capable of becoming pregnant
unless the female patient cannot have children because of surgery or other medical
reasons (effective tubal ligation, ovaries or the uterus removed, or are
post-menopausal). Post-menopausal is defined as:

- Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments,

- LH and FSH levels in the post menopausal range for women under 50,

- radiation-induced oophorectomy with last menses >1 year ago,

- chemotherapy-induced menopause with >1 year interval since last menses,

- or surgical sterilization (bilateral oophorectomy or hysterectomy).

- Negative urine pregnancy test less than or equal to 3 days prior to C1D1 (women of
childbearing potential only)

- Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

Inclusion Criteria Phase II - SCLC:

- Age greater than or equal to18 years.

- Patients must have histologically or cytologically confirmed diagnosis of SCLC from a
CLIA-certified laboratory.

- Have received and progressed during or after a platinum-based standard chemotherapy
regimen and/or an immune-checkpoint inhibitor.

- Patients could have received any number of therapies for relapsed or progressive
disease, including re-treatment with original frontline regimen. A minimum of 2 weeks
will be required from any prior therapy, including chemotherapy, immunotherapy and/or
radiation. In addition, recovery to Grade less than or equal to 1 from all reversible
toxicities related to prior therapy is required at study entry. No previous
irradiation to the site of measurable or evaluable disease, unless that site had
subsequent evidence of progression.

- Patients must have measurable disease as per Response Evaluation Criteria in Solid
Tumors, version (RECIST 1.1).

- Radiographic evidence of disease progression after initial therapy should have been
documented.

- ECOG performance status less than or equal to 2.

- Patients with treated brain metastases (surgery, whole or stereotactic brain
radiation) are allowed provided the lesions have been stable for at least 2 weeks and
the patient is off steroids or is on a stable dose of steroids. Patients with brain
metastases should not require use of enzyme-inducing antiepileptic drugs (e.g.,
carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and
during study. Use of newer antiepileptics that do not produce enzyme induction
drug-drug interactions (DDIs) is allowed.

- 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 without growth
factor support

- platelets greater than or equal to 100,000/mcL without growth factor support

- hemoglobin greater than or equal to 9 gr/dl and no blood transfusion within 4
weeks OR greater than 10 g/dL and no blood transusion within 2 weeks

- total bilirubin less than or equal to 1.5 x ULN (unless Gilbert s Disease)

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of
normal (less than or equal to 5X ULN if liver mets)

- creatinine less than ULN OR

- creatinine clearance greater than or equal to 51 mL/min (calculated using the
Cockroft- Gault formula) for patients with creatinine levels above institutional
normal.

- The effects of CRLX101 and olaparib on the developing human fetus are unknown. For
this reason and because these agents are known to be teratogenic, women of
childbearing potential and men must agree to use highly effective contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation and for 120 days (both male and female) following
last dose of study drug. 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. Fertile females of childbearing potential are defined
as women physically capable of becoming pregnant unless the female patient cannot have
children because of surgery or other medical reasons (effective tubal ligation,
ovaries or the uterus removed, or are post-menopausal). Post-menopausal is defined as:

- Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments,

- LH and FSH levels in the post menopausal range for women under 50,

- radiation-induced oophorectomy with last menses >1 year ago,

- chemotherapy-induced menopause with >1 year interval since last menses,

- or surgical sterilization (bilateral oophorectomy or hysterectomy).

INCLUSION CRITERIA FOR UROTHELIAL CARCINOMA EXPANSION COHORT:

- Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the
bladder, urethra, ureter, or renal pelvis from a CLIA-certified laboratory, with
measurable disease by RECIST including lymphadenopathy and visceral metastatic
disease.

- Male or female patients greater than or equal to 18 years of age.

- Patient must have received at least one platinum based regimen of chemotherapy and/or
an immune-checkpoint inhibitor if appropriate with progressive disease.

- Prior antiangiogenic therapy are permitted (2-week washout from therapy is required).

- Bisphosphonates and denosumab are permitted if on a stable dose for greater than equal
to 4 weeks.

- ECOG 0 2

- 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 without growth factor
support

- platelets greater than or equal to 100,000/mcL without growth factor support

- hemoglobin greater than or equal to 10 g/dL in the absence of packed red blood cells
transfusion 28 days prior to dosing OR

- hemoglobin >9 g/dL, if the value is constant across 2 readings within 2 weeks in the
absence of packed red blood cells transfusion 28 days prior to dosing

- total bilirubin less than or equal to 1.5 x ULN (less than or equal to 3 (SqrRoot) ULN
for subjects with Gilbert s Disease)

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal
(less than or equal to 5X ULN if liver mets)

- creatinine less than or equal to ULN OR

- creatinine clearance greater than or equal to 51 mL/min (calculated using the
Cockroft-Gault formula) for patients with creatinine levels above institutional
normal.

- PT/INR and aPTT within 1.25 X ULN institutional limits, except where a lupus
anti-coagulant has been confirmed

- The effects of CRLX101 and olaparib on the developing human fetus are unknown. For
this reason and because these agents are known to be teratogenic, women of
childbearing potential and men must agree to use highly effective contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation and for 120 days (both male and female) following
last dose of study drug. 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. Fertile females of childbearing potential are defined
as women physically capable of becoming pregnant unless the female patient cannot have
children because of surgery or other medical reasons (effective tubal ligation,
ovaries or the uterus removed, or are post-menopausal). Post-menopausal is defined as:

- Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments,

- LH and FSH levels in the post menopausal range for women under 50,

- radiation-induced oophorectomy with last menses >1 year ago,

- chemotherapy-induced menopause with >1 year interval since last menses, or
surgical sterilization (bilateral oophorectomy or hysterectomy).

- Patients must be able to tolerate oral medications and not have gastrointestinal
illnesses that would preclude absorption of olaparib.

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

- Willingness to release archival tissue sample for research purposes, if available

INCLUSION CRITERIA FOR mCRPC EXPANSION COHORT:

- Patients must have metastatic, progressive, castrate resistant prostate cancer
(mCRPC).

- Documented histopathological confirmation of prostate cancer from a CLIA-certified
laboratory.

- All patients must have at least one lesion deemed safe to biopsy and be willing to
undergo a mandatory baseline biopsy.

- Patients must have received prior treatment with enzalutamide and/or abiraterone with
the exception of patients who were treated with docetaxel and androgen deprivation
therapy for metastatic castrate-sensitive prostate cancer and progressed on docetaxel
treatment or who progress within one month of the last docetaxel dose.

- Patients must have castrate levels of testosterone (<50 ng/dl [1.74 nmol/l])

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

- ECOG performance status less than or equal to 2

- Patients must have adequate bone marrow, hepatic, and renal function with:

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

- absolute neutrophil count greater than or equal to 1,500/mcL without growth factor
support

- platelets greater than or equal to 100,000/mcL without growth factor support

- hemoglobin greater than or equal to 9 g/dL

- total bilirubin less than or equal to 1.5 x ULN (less than or equal to 3 (SqrRoot) ULN
for subjects with Gilbert s Disease)

- AST(SGOT)/ALT(SGPT) <3 X institutional upper limit of normal (less than or equal to 5X
ULN if liver mets)

- creatinine less than or equal to ULN OR

- creatinine clearance greater than or equal to 51 mL/min (calculated using the
Cockroft-Gault formula) for patients with creatinine levels above institutional
normal.

- Men must be at least 18 years of age.

- Patient must be capable of understanding and complying with protocol requirements
and is willing to give informed consent.

- Men treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study and for the duration of study participation and for 120 days after
last dose of study drug. Sexually active subjects and their female partners must agree
to use medically accepted barrier methods of contraception (e.g., male or female
condom) during the course of the study and for 3 months after the last dose of study
drug(s), even if oral contraceptives are also used. All subjects of reproductive
potential must also agree to use both a barrier method and a second method of birth
control during the course of the study and for 3 months after the last dose of study
drug(s). Should a woman become pregnant or suspect she is pregnant while her partner
is participating in this study, she should i...