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 dose escalation study of ROR1 CAR-specific autologous T-lymphocytes.

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):

- Patients with non-small cell lung cancer that is metastatic or inoperable and who have
been treated with at least one line of prior therapy or declined conventional therapy

- 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)

- Patients must have measurable disease by at least one of the criteria below:

- Extra skeletal disease that can be accurately measured in at least one dimension
as >= 10 mm with conventional computed tomography (CT) techniques as defined by
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

- Skeletal or bone-only disease measurable by fludeoxyglucose F 18 (FDG) positron
emission tomography (PET) imaging

- ROR1 expression in > 20% of the primary tumor or metastasis by immunohistochemistry
(IHC)

- Karnofsky performance status of >= 70%

- 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

- 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 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])

- Patients must have measurable disease by at least one of the criteria below:

- Extra skeletal disease that can be accurately measured in at least one dimension
as >= 10 mm with conventional CT techniques as defined by RECIST 1.1

- Skeletal or bone-only disease measurable by FDG PET imaging

- 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

- Patients may receive agents to protect against skeletal related complications such as
zoledronic acid or denosumab

- ROR1 expression in > 20% of the primary tumor or metastasis by IHC

- Karnofsky performance status of >= 70%

- Patients must be off chemotherapy for a minimum of 3 weeks prior to planned
leukapheresis

- 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

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 ongoing daily corticosteroid therapy at a dose of > 15 mg of
prednisone per day (or equivalent); pulsed corticosteroid use for disease control is
acceptable

- 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 =< 65% 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

- 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

- Untreated 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):

- Absolute neutrophil count (ANC) < 1000/mm^3

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

- Platelet count < 75,000/mm^3

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

- Patients requiring ongoing daily corticosteroid therapy at a dose of > 15 mg of
prednisone per day (or equivalent); pulsed corticosteroid use for disease control is
acceptable

- Active autoimmune disease requiring immunosuppressive therapy

- Serum creatinine > 2.5 mg/dL

- 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 an
FEV1 of =< 65% or 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 EF of
45-49% must receive clearance by a cardiologist to be eligible for the trial

- Patients who are 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

- Women who are breastfeeding

- 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

- Untreated 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:

- ANC < 1000/mm^3

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

- Platelet count < 75,000/mm^3

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

- Patients requiring ongoing daily corticosteroid therapy at a dose of > 15 mg of
prednisone per day (or equivalent); pulsed corticosteroid use for disease control is
acceptable

- Active autoimmune disease requiring immunosuppressive therapy

- Serum creatinine > 2.5 mg/dL

- 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 an
FEV1 of =< 65% or 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 EF of
45-49% must receive clearance by a cardiologist to be eligible for the trial

- Patients who are 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

- Breast-feeding women

- Patients who have contraindication to cyclophosphamide chemotherapy

- 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

- Untreated 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