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

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

Status
Terminated
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02706392
Enrollment
21
Registered
2016-03-11
Start date
2016-03-16
Completion date
2021-09-28
Last updated
2022-08-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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 IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7, Stage III Lung Non-Small Cell Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7, Stage IV Lung Non-Small Cell Cancer AJCC v7, Unresectable Lung Non-Small Cell Carcinoma

Brief summary

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

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.

Interventions

OTHERLaboratory Biomarker Analysis

Correlative studies

BIOLOGICALROR1 CAR-specific Autologous T-Lymphocytes

Given IV

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
Fred Hutchinson Cancer Center
Lead SponsorOTHER

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

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

Design outcomes

Primary

MeasureTime frameDescription
Number of Participants That Experienced Adverse EventsWithin 35 days of receptor tyrosine kinase-like orphan receptor 1 positive chimeric antigen receptor-T cell infusionWill 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.

Secondary

MeasureTime frameDescription
Number of Participants With Persistence of Adoptively Transferred Receptor Tyrosine Kinase-like Orphan Receptor 1 Positive Chimeric Antigen Receptor-T CellsUp to 28 days after the T cell infusionData 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.
Number of Participants Biopsied With Detectable CD3 T-cellsUp to 48 days post infusionSamples 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.
Objective Response Rate of Complete Remission and Partial RemissionUp to 1 yearOutcome 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.
Progression Free SurvivalUp to 1 yearOutcome 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.
Overall SurvivalUp to 1 yearData 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.

Countries

United States

Participant flow

Participants by arm

ArmCount
Cohort A Dose Level 1
Patients with ROR1+ CLL, MCL or ALL that are refractory to conventional therapy will be eligible for Cohort A. Dose level 1 will be up to 3.3x105 EGFRt+ cells/kg. This is the starting dose for the study.
2
Cohort A Dose Level 2
Patients with ROR1+ CLL, MCL or ALL that are refractory to conventional therapy will be eligible for Cohort A. Dose level 2 will be up to 1x106 EGFRt+ cells/kg.
1
Cohort B Dose Level 1
Patients with ROR1+ NSCLC or TNBC who have failed conventional chemotherapy or targeted therapy, or for whom these therapies are not effective will be eligible for Cohort B. Dose level 1 will be up to 3.3x105 EGFRt+ cells/kg. This is the starting dose for the study.
2
Cohort B Dose Level 2
Patients with ROR1+ NSCLC or TNBC who have failed conventional chemotherapy or targeted therapy, or for whom these therapies are not effective will be eligible for Cohort B. Dose level 2 will be up to 1x106 EGFRt+ cells/kg.
3
Cohort B Dose Level 3
Patients with ROR1+ NSCLC or TNBC who have failed conventional chemotherapy or targeted therapy, or for whom these therapies are not effective will be eligible for Cohort B. Dose level 3 will be up to 3.3x106 EGFRt+ cells/kg.
11
Cohort B Dose Level 4
Patients with ROR1+ NSCLC or TNBC who have failed conventional chemotherapy or targeted therapy, or for whom these therapies are not effective will be eligible for Cohort B. Dose level 4 will be up to 1.0x107 EGFRt+ cells/kg
2
Total21

Withdrawals & dropouts

PeriodReasonFG000FG001FG002FG003FG004FG005
Overall StudyDeath102252

Baseline characteristics

CharacteristicTotalCohort A Dose Level 2Cohort B Dose Level 1Cohort B Dose Level 2Cohort A Dose Level 1Cohort B Dose Level 3Cohort B Dose Level 4
Age, Categorical
<=18 years
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
>=65 years
7 Participants1 Participants0 Participants1 Participants1 Participants4 Participants0 Participants
Age, Categorical
Between 18 and 65 years
14 Participants0 Participants2 Participants2 Participants1 Participants7 Participants2 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
17 Participants1 Participants2 Participants3 Participants2 Participants9 Participants0 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
4 Participants0 Participants0 Participants0 Participants0 Participants2 Participants2 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
1 Participants0 Participants0 Participants0 Participants0 Participants1 Participants0 Participants
Race (NIH/OMB)
Black or African American
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
1 Participants0 Participants0 Participants0 Participants0 Participants1 Participants0 Participants
Race (NIH/OMB)
White
19 Participants1 Participants2 Participants3 Participants2 Participants9 Participants2 Participants
Region of Enrollment
United States
21 participants1 participants2 participants3 participants2 participants11 participants2 participants
Sex: Female, Male
Female
13 Participants0 Participants2 Participants2 Participants0 Participants8 Participants1 Participants
Sex: Female, Male
Male
8 Participants1 Participants0 Participants1 Participants2 Participants3 Participants1 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
EG004
affected / at risk
EG005
affected / at risk
deaths
Total, all-cause mortality
1 / 20 / 12 / 22 / 35 / 112 / 2
other
Total, other adverse events
2 / 21 / 12 / 23 / 311 / 112 / 2
serious
Total, serious adverse events
1 / 21 / 11 / 22 / 310 / 112 / 2

Outcome results

Primary

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.

Time frame: Within 35 days of receptor tyrosine kinase-like orphan receptor 1 positive chimeric antigen receptor-T cell infusion

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Cohort A Dose Level 1Number of Participants That Experienced Adverse Events2 Participants
Cohort A Dose Level 2Number of Participants That Experienced Adverse Events1 Participants
Cohort B Dose Level 1Number of Participants That Experienced Adverse Events2 Participants
Cohort B Dose Level 2Number of Participants That Experienced Adverse Events3 Participants
Cohort B Dose Level 3Number of Participants That Experienced Adverse Events11 Participants
Cohort B Dose Level 4Number of Participants That Experienced Adverse Events2 Participants
Secondary

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.

Time frame: Up to 48 days post infusion

Population: Participants were analyzed if there was a biopsy done within 48 days post infusion. Biopsies were performed on 10 participants total, 2 participants in Cohort A and 8 participants in Cohort B.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Cohort A Dose Level 1Number of Participants Biopsied With Detectable CD3 T-cells2 Participants
Cohort A Dose Level 2Number of Participants Biopsied With Detectable CD3 T-cells0 Participants
Cohort B Dose Level 1Number of Participants Biopsied With Detectable CD3 T-cells2 Participants
Cohort B Dose Level 2Number of Participants Biopsied With Detectable CD3 T-cells1 Participants
Cohort B Dose Level 3Number of Participants Biopsied With Detectable CD3 T-cells0 Participants
Cohort B Dose Level 4Number of Participants Biopsied With Detectable CD3 T-cells0 Participants
Secondary

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.

Time frame: Up to 28 days after the T cell infusion

Population: Number analyzed is the number of participants that were evaluated for persistence in each arm. 2 patients were excluded because they went off study before their 1 month post treatment evaluation and were not assessed for persistence. 1 of these patients was in cohort A DL2. The other was in Cohort B DL4.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Cohort A Dose Level 1Number of Participants With Persistence of Adoptively Transferred Receptor Tyrosine Kinase-like Orphan Receptor 1 Positive Chimeric Antigen Receptor-T Cells2 Participants
Cohort A Dose Level 2Number of Participants With Persistence of Adoptively Transferred Receptor Tyrosine Kinase-like Orphan Receptor 1 Positive Chimeric Antigen Receptor-T Cells0 Participants
Cohort B Dose Level 1Number of Participants With Persistence of Adoptively Transferred Receptor Tyrosine Kinase-like Orphan Receptor 1 Positive Chimeric Antigen Receptor-T Cells2 Participants
Cohort B Dose Level 2Number of Participants With Persistence of Adoptively Transferred Receptor Tyrosine Kinase-like Orphan Receptor 1 Positive Chimeric Antigen Receptor-T Cells1 Participants
Cohort B Dose Level 3Number of Participants With Persistence of Adoptively Transferred Receptor Tyrosine Kinase-like Orphan Receptor 1 Positive Chimeric Antigen Receptor-T Cells0 Participants
Cohort B Dose Level 4Number of Participants With Persistence of Adoptively Transferred Receptor Tyrosine Kinase-like Orphan Receptor 1 Positive Chimeric Antigen Receptor-T Cells0 Participants
Secondary

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.

Time frame: Up to 1 year

Population: In arm 1, one patient was not assessed for a response and therefore is not included in the number of participants analyzed count.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Cohort A Dose Level 1Objective Response Rate of Complete Remission and Partial Remission0 Participants
Cohort A Dose Level 2Objective Response Rate of Complete Remission and Partial Remission0 Participants
Cohort B Dose Level 1Objective Response Rate of Complete Remission and Partial Remission0 Participants
Cohort B Dose Level 2Objective Response Rate of Complete Remission and Partial Remission1 Participants
Cohort B Dose Level 3Objective Response Rate of Complete Remission and Partial Remission0 Participants
Cohort B Dose Level 4Objective Response Rate of Complete Remission and Partial Remission0 Participants
Secondary

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.

Time frame: Up to 1 year

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Cohort A Dose Level 1Overall Survival1 Participants
Cohort A Dose Level 2Overall Survival1 Participants
Cohort B Dose Level 1Overall Survival0 Participants
Cohort B Dose Level 2Overall Survival1 Participants
Cohort B Dose Level 3Overall Survival6 Participants
Cohort B Dose Level 4Overall Survival0 Participants
Secondary

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.

Time frame: Up to 1 year

Population: Only participants that survived up to 1 year post-infusion (per patient) could be analyzed for this outcome. In arm 1, one patient survived up to 1 year but they were not assessed for a response, therefore are not included in the number of participants analyzed count.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Cohort A Dose Level 1Progression Free Survival0 Participants
Cohort A Dose Level 2Progression Free Survival0 Participants
Cohort B Dose Level 1Progression Free Survival0 Participants
Cohort B Dose Level 2Progression Free Survival0 Participants
Cohort B Dose Level 3Progression Free Survival1 Participants
Cohort B Dose Level 4Progression Free Survival0 Participants

Source: ClinicalTrials.gov · Data processed: Feb 27, 2026