Genetically Modified T-Cell Therapy in Treating Patients With Advanced ROR1+ Malignancies

PRIMARY OBJECTIVES:

I. To evaluate the safety of adoptive T cell therapy using ex vivo expanded autologous
cluster of differentiation (CD)8+ and CD4+ ROR1 CAR-T cells for patients with advanced ROR1+
hematologic (Cohort A) and epithelial (Cohort B) malignancies.

SECONDARY OBJECTIVES:

I. To determine duration of in vivo persistence of adoptively transferred T cells, and the
phenotype of persisting T cells.

II. To determine trafficking of adoptively transferred T cells traffic to the bone marrow or
other tumor site and function in vivo.

III. To determine preliminary antitumor activity of the adoptive transfer of ROR1 CAR-T
cells in patients with measurable tumor burden prior to T cell transfer.

OUTLINE: This is a phase I, dose escalation study of ROR1 CAR-specific autologous
T-lymphocytes followed by a phase II study.

Patients receive chemotherapy comprising fludarabine phosphate and cyclophosphamide as
determined by the referring physician in consultation with the protocol principal
investigator (PI). Beginning within 36-96 hours after completion of lymphodepleting
chemotherapy, patients receive ROR1 CAR-specific autologous T-lymphocytes intravenously (IV)
over 20-30 minutes. Patients may receive a second infusion of ROR1 CAR-specific autologous
T-lymphocytes with or without additional cytoreductive therapy at the same (for those that
received the highest cell dose) or up to the next highest dose level and there is persistent
disease, there were no toxicities attributed to the first infusion, and the patient is at
least 21 days from the first T cell infusion.

After completion of study treatment, patients are followed up for at least 15 years.

Inclusion Criteria:

- INCLUSION CRITERIA FOR PATIENTS WITH CLL, MCL OR ALL (COHORT A)

- CLL who are beyond first remission and who have failed combination chemoimmunotherapy
with regimens containing a purine analogue and anti-CD20 antibody, or who have failed
tyrosine kinase or phosphatidylinositol 3 (PI3) kinase inhibitors, or who were not
eligible for or declined such therapy; patients with fludarabine refractory disease
are eligible

- Mantle cell lymphoma patients who are beyond first remission and previously treated
with chemoimmunotherapy; patients who have relapsed following autologous
hematopoietic cell transplant (HCT) are eligible

- ALL patients who have relapsed or have residual disease following treatment with
curative intent; ALL patients must have ROR1 expressed on > 90% of the leukemia
blasts to be eligible

- Confirmation of diagnosis by internal pathology review of initial or subsequent
biopsy or other pathologic material at the Fred Hutchinson Cancer Research Center
(FHCRC)/Seattle Cancer Care Alliance (SCCA)

- Evidence of ROR1 expression by immunohistochemistry or flow cytometry on any prior or
current tumor specimen

- Karnofsky performance status >= 70%

- Negative pregnancy test for women of childbearing potential; subjects of childbearing
potential are those who have not been surgically sterilized or have not been free
from menses for > 1 year

- Fertile male and female patients must be willing to use a contraceptive method
before, during, and for at least two months after the T cell infusion

- Ability to understand and provide informed consent

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B):

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients with stage IV
non-small cell lung cancer who have been treated with at least one line of prior
therapy or declined conventional therapy

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients with known
epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations
must have been treated on at least one line of molecularly targeted therapy (e.g.,
erlotinib, crizotinib)

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients must have
measurable disease as described below

- Extra skeletal disease that can be accurately measured in at least one dimension
as >= 10 mm with conventional computed tomography (CT) techniques

- Skeletal or bone-only disease that is measurable by fludeoxyglucose F 18 (FDG)
positron emission tomography (PET) imaging will also be allowed

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): ROR1 expression in >
20% of the primary tumor or metastasis by immunohistochemistry (IHC)

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Karnofsky performance
status of >= 70%

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients must be off
chemotherapy for a minimum of 3 weeks prior to start of treatment; targeted therapies
must be stopped at least 3 days prior to start of lymphodepletion

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Negative pregnancy
test for women of childbearing potential; subjects of childbearing potential are
those who have not been surgically sterilized or have not been free from menses for >
1 year

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Fertile male and
female patients must be willing to use a contraceptive method before, during and for
at least two months after the T cell infusion

- INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Ability to understand
and provide informed consent

- INCLUSION CRITERIA FOR TNBC

- INCLUSION CRITERIA FOR TNBC: Histologically confirmed diagnosis of metastatic TNBC;
i.e. breast cancer that is estrogen receptor (ER) negative (=< 10%), progesterone
receptor (PR) negative (=< 10%), and human epidermal growth factor receptor 2 (HER2)
negative (0 or 1+ by immunohistochemistry or negative for gene amplification by
fluorescence in situ hybridization [FISH])

- INCLUSION CRITERIA FOR TNBC: Patients must have measurable disease as defined by
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

- INCLUSION CRITERIA FOR TNBC: Patients must have received standard adjuvant,
neoadjuvant, and/or metastatic chemotherapy per National Comprehensive Cancer Network
(NCCN) or institutional practice; no maximum on number of prior systemic treatment
regimens

- INCLUSION CRITERIA FOR TNBC: Patients may receive agents to protect against skeletal
related complications such as zolendronic acid or denosumab

- INCLUSION CRITERIA FOR TNBC: ROR1 expression in > 20% of the primary tumor or
metastasis by IHC

- INCLUSION CRITERIA FOR TNBC: Karnofsky performance status of >= 70%

- INCLUSION CRITERIA FOR TNBC: Patients must be off chemotherapy for a minimum of 3
weeks prior to planned leukapheresis

- INCLUSION CRITERIA FOR TNBC: Negative pregnancy test for women of childbearing
potential; subjects of childbearing potential are those who have not been surgically
sterilized or have not been free from menses for > 1 year

- INCLUSION CRITERIA FOR TNBC: Fertile male and female patients must be willing to use
a contraceptive method before, during and for at least two months after the T cell
infusion

- INCLUSION CRITERIA FOR TNBC: Ability to understand and provide informed consent

Exclusion Criteria:

- EXCLUSION CRITERIA FOR PATIENTS WITH CLL, MCL, OR ALL (COHORT A)

- Treatment with other investigational agent(s) within 30 days of planned
lymphodepletion

- Patients requiring corticosteroid therapy at a dose of > 15 mg of prednisone per day
(or equivalent)

- Active autoimmune disease requiring immunosuppressive therapy

- Serum creatinine > 2.5 mg/dL

- Serum glutamic oxaloacetic transaminase (SGOT) > 5 x upper limit of normal

- Bilirubin > 3.0 mg/dL

- Patients with clinically significant pulmonary dysfunction, as determined by medical
history and physical exam should undergo pulmonary function testing; those with a
forced expiratory volume in 1 second (FEV1) of < 2.0 L or diffusion capacity of the
lung for carbon monoxide (DLCO) (corrected) < 40% will be excluded

- Significant cardiovascular abnormalities as defined by any one of the following:
congestive heart failure, clinically significant hypotension, symptomatic coronary
artery disease, or a documented ejection fraction of < 45%; any patient with an
ejection fraction (EF) of 45-49% must receive clearance by a cardiologist to be
eligible for the trial

- Patients who are human immunodeficiency virus (HIV) seropositive

- Uncontrolled active infection (bacterial, viral, fungal, mycobacterial) not
responding to treatment with intravenous antibiotics, antiviral or antifungal agents,
or long-term treatment with oral agents

- Anticipated survival of < 3 months

- Women who are breast-feeding

- Patients who have contraindication to cyclophosphamide chemotherapy

- Known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy

- Active central nervous system (CNS) metastases and/or carcinomatous meningitis;
subjects with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least four weeks prior to
enrollment and any neurologic symptoms have returned to baseline), have no evidence
of new or enlarging brain metastases

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B)

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Absolute neutrophil
count (ANC) < 1000/mm^3

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Hemoglobin (Hgb) < 9
mg/dl (transfusion permitted to achieve this)

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Platelet count <
75,000/mm^3

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Treatment with other
investigational agent(s) within 30 days of planned lymphodepletion

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients requiring
corticosteroid therapy at a dose of > 15 mg of prednisone per day (or equivalent)

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Active autoimmune
disease requiring immunosuppressive therapy

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Serum creatinine > 2.5
mg/dL

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): SGOT > 5 x upper limit
of normal

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): bilirubin > 3.0 mg/dL

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients with
clinically significant pulmonary dysfunction, as determined by medical history and
physical exam should undergo pulmonary function testing; those with an FEV1 of < 2.0
L or DLCO (corrected) < 40% will be excluded

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Significant
cardiovascular abnormalities as defined by any one of the following: congestive heart
failure, clinically significant hypotension, symptomatic coronary artery disease, or
a documented ejection fraction of < 45%; any patient with an EF of 45-49% must
receive clearance by a cardiologist to be eligible for the trial

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients who are HIV
seropositive

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Uncontrolled active
infection (bacterial, viral, fungal, mycobacterial) not responding to treatment with
intravenous antibiotics, antiviral or antifungal agents, or long-term treatment with
oral agents

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Women who are
breastfeeding

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Anticipated survival
of < 3 months

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients who have
contraindication to cyclophosphamide chemotherapy

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Known additional
malignancy that is progressing or requires active treatment; exceptions include basal
cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical
cancer that has undergone potentially curative therapy

- EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Active central nervous
system (CNS) metastases and/or carcinomatous meningitis; subjects with previously
treated brain metastases may participate provided they are stable (without evidence
of progression by imaging for at least four weeks prior to enrollment and any
neurologic symptoms have returned to baseline), have no evidence of new or enlarging
brain metastases

- EXCLUSION CRITERIA FOR TNBC

- EXCLUSION CRITERIA FOR TNBC: ANC < 1000/mm^3

- Hgb < 9 mg/dl (transfusion permitted to achieve this)

- EXCLUSION CRITERIA FOR TNBC: Platelet count < 75,000/mm^3

- EXCLUSION CRITERIA FOR TNBC: Treatment with other investigational agent(s) within 30
days of planned lymphodepletion

- EXCLUSION CRITERIA FOR TNBC: Patients requiring corticosteroid therapy at a dose of >
15 mg of prednisone per day (or equivalent)

- EXCLUSION CRITERIA FOR TNBC: Active autoimmune disease requiring immunosuppressive
therapy

- EXCLUSION CRITERIA FOR TNBC: Serum creatinine > 2.5 mg/dL

- EXCLUSION CRITERIA FOR TNBC: SGOT > 5 x upper limit of normal

- EXCLUSION CRITERIA FOR TNBC: Bilirubin > 3.0 mg/dL

- EXCLUSION CRITERIA FOR TNBC: Patients with clinically significant pulmonary
dysfunction, as determined by medical history and physical exam should undergo
pulmonary function testing; those with an FEV1 of < 2.0 L or DLCO (corrected) < 40%
will be excluded

- EXCLUSION CRITERIA FOR TNBC: Significant cardiovascular abnormalities as defined by
any one of the following: congestive heart failure, clinically significant
hypotension, symptomatic coronary artery disease or a documented ejection fraction of
< 45%; any patient with an EF of 45-49% must receive clearance by a cardiologist to
be eligible for the trial

- EXCLUSION CRITERIA FOR TNBC: Patients who are HIV seropositive

- EXCLUSION CRITERIA FOR TNBC: Uncontrolled active infection (bacterial, viral, fungal,
mycobacterial) not responding to treatment with intravenous antibiotics, antiviral or
antifungal agents, or long-term treatment with oral agents

- EXCLUSION CRITERIA FOR TNBC: Anticipated survival of < 3 months

- EXCLUSION CRITERIA FOR TNBC: Breast-feeding women

- EXCLUSION CRITERIA FOR TNBC: patients who have contraindication to cyclophosphamide
chemotherapy

- EXCLUSION CRITERIA FOR TNBC: Has a known additional malignancy that is progressing or
requires active treatment; exceptions include basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone
potentially curative therapy

- EXCLUSION CRITERIA FOR TNBC: Has known active central nervous system (CNS) metastases
and/or carcinomatous meningitis; subjects with previously treated brain metastases
may participate provided they are stable (without evidence of progression by imaging
for at least four weeks prior to enrollment and any neurologic symptoms have returned
to baseline) and have no evidence of new or enlarging brain metastases