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

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of genetically modified T-cell therapy in treating patients with receptor tyrosine kinase-like orphan receptor 1 positive (ROR1+) chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), stage IV non-small cell lung cancer (NSCLC), or triple negative breast cancer (TNBC) that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Genetically modified therapies, such as ROR1 specific chimeric antigen receptor (CAR) T-cells, are taken from a patient's blood, modified in the laboratory so they specifically may kill cancer cells with a protein called ROR1 on their surfaces, and safely given back to the patient after conventional therapy. The genetically modified T-cells have genes added in the laboratory to make them recognize ROR1.

Detailed Description
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PRIMARY OBJECTIVE: 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.

Official Title
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Phase I Study of Adoptive Immunotherapy for Advanced ROR1+ Malignancies With Defined Subsets of Autologous T Cells Engineered to Express a ROR1-Specific Chimeric Antigen Receptor

Conditions
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Stage IV Breast Cancer AJCC v6 and v7, Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Acute Lymphoblastic Leukemia, Recurrent Mantle Cell Lymphoma, Refractory Chronic Lymphocytic Leukemia, Stage III Lung Non-Small Cell Cancer AJCC v7, Stage IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7, Stage IV Lung Non-Small Cell Cancer AJCC v7, Unresectable Lung Non-Small Cell Carcinoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Biological: ROR1 CAR-specific Autologous T-Lymphocytes


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ROR1 CAR-specific autologous T-lymphocytes)<br>Patients receive chemotherapy comprising fludarabine phosphate and cyclophosphamide as determined by the referring physician in consultation with the protocol PI. Beginning within 36-96 hours after completion of lymphodepleting chemotherapy, patients receive ROR1 CAR-specific autologous T-lymphocytes 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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: ROR1 CAR-specific Autologous T-Lymphocytes<br>* Given IV<br>* Other names: ROR1-CAR-T;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Experienced Adverse Events | Will be graded according to Common Terminology Criteria for Adverse Events. Outcome will be reported as a count of participants that experienced adverse events in each arm. | Within 35 days of receptor tyrosine kinase-like orphan receptor 1 positive chimeric antigen receptor-T cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Persistence of Adoptively Transferred Receptor Tyrosine Kinase-like Orphan Receptor 1 Positive Chimeric Antigen Receptor-T Cells | Data should be collected for persistence of transferred T cells and descriptive statistics will be used to summarize the changes from baseline where possible. This outcome is reported as a count of participants who experienced persistence at Day 28. | Up to 28 days after the T cell infusion | 
| Number of Participants Biopsied With Detectable CD3 T-cells | Samples of bone marrow, blood and other tissues (e.g. cerebral spinal fluid, tumor, thoracentesis fluid) will be collected from patients as clinically indicated. CD3 T-cells and their frequency/persistence will be detected by flow cytometry, polymerase chain reaction, and immunohistochemistry as appropriate. This outcome is reported as a count of participants who had detectable CD3 T-cells in their biopsy sample. The patients in Cohort A had a biopsy of their bone marrow. For the patients in Cohort B, biopsy location was dependent on site of disease per patient. | Up to 48 days post infusion | 
| Objective Response Rate of Complete Remission and Partial Remission | Outcome will be reported as a count of participants in each arm that experienced complete remission and/or partial remission. For Patients with Acute lymphoblast leukemia (ALL), remission status will be determined by restaging of bone marrow and other involved sites by morphology, flow cytometry and molecular studies, as appropriate. For Patients with NSCLC and TNBC, tumor response and progression will be evaluated in this study using the international criteria proposed by RECIST Criteria. Target lesion responses will be described as (1) Complete response (CR): disappearance of all target lesions; (2) Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and, (4) Stable Disease: neither sufficient shrinkage to qualify for PR nor sufficient growth to qualify for PD. | Up to 1 year | 
| Progression Free Survival | Outcome will be reported as a count of participants in each arm that survived up to 1 year post-infusion (per patient) and did not progress. For patients with Acute lymphoblast leukemia (ALL), remission status will be determined by restaging of bone marrow and other involved sites by morphology, flow cytometry and molecular studies, as appropriate. For Patients with NSCLC and TNBC, tumor response and progression will be evaluated in this study using the international criteria proposed by RECIST Criteria. Target lesion responses will be described as (1) Complete response (CR): disappearance of all target lesions; (2) Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and, (4) Stable Disease: neither sufficient shrinkage to qualify for PR nor sufficient growth to qualify for PD. | Up to 1 year | 
| Overall Survival | Data should be collected for efficacy of transferred T cells and descriptive statistics will be used to summarize the changes from baseline where possible. Outcome will be reported as a count of participants that survived up until the 1 year post-infusion (per patient) timepoint. | Up to 1 year |