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Hematopoietic and Lymphoid Cell NeoplasmPhase 1NCT02706392

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

A Phase 1 study testing Laboratory Biomarker Analysis and ROR1 CAR-specific Autologous T-Lymphocytes in people with Hematopoietic and Lymphoid Cell Neoplasm and Malignant Solid Neoplasm, run by Fred Hutchinson Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Laboratory Biomarker Analysis and ROR1 CAR-specific Autologous T-Lymphocytes
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
21 participants
Where
1 siteUnited States
Study dates
16 Mar 2016to 28 Sep 2021
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 34Show fewer
  • 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
  • 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

Who cannot join

  • 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
Show all 50Show fewer
  • 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
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Fred Hutch/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

Official title: 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

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. 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:

  1. 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.

Being tested
Laboratory Biomarker Analysis, ROR1 CAR-specific Autologous T-Lymphocytes
Medical subject headings
Hematologic Neoplasms, Carcinoma, Non-Small-Cell Lung, Triple Negative Breast Neoplasms, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Lymphoma, Mantle-Cell, Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • ROR1 CAR-specific Autologous T-LymphocytesBiological

    Also called Autologous ROR1-CAR-T Cells, Chimeric Anti-ROR1 T-cell Receptor-expressing Autologous T-lymphocytes, ROR1-CAR-T

    Given IV

Study groups in NCT02706392
Study groupRoleWhat they receive
Treatment (ROR1 CAR-specific autologous T-lymphocytes)ExperimentalPatients 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.
Receives: Other: Laboratory Biomarker Analysis; Biological: ROR1 CAR-specific Autologous T-Lymphocytes

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

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

Secondary outcomes (5)

  1. 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.

    Measured: Up to 28 days after the T cell infusion

  2. 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.

    Measured: Up to 48 days post infusion

  3. 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.

    Measured: Up to 1 year

  4. 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.

    Measured: Up to 1 year

  5. 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.

    Measured: Up to 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Mar 2016 (estimated)
  2. Study start16 Mar 2016
  3. Primary completion17 May 2021
  4. Study completion28 Sep 2021

Why it stopped: Terminated due to slow accruals.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
21 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02706392
Sponsor's protocol ID
9330
Other IDs
NCI-2015-01753, 9330, RG9215045, 2R01CA114536
Status last verified
Aug 2022
First submitted
1 Mar 2016
Last updated
31 Aug 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Osorio-Rodriguez DA, Camacho BA, Ramirez-Segura C. Anti-ROR1 CAR-T cells: Architecture and performance. Front Med (Lausanne). 2023 Feb 17;10:1121020. doi: 10.3389/fmed.2023.1121020. eCollection 2023.

    PubMed 36873868

  • Srivastava S, Furlan SN, Jaeger-Ruckstuhl CA, Sarvothama M, Berger C, Smythe KS, Garrison SM, Specht JM, Lee SM, Amezquita RA, Voillet V, Muhunthan V, Yechan-Gunja S, Pillai SPS, Rader C, Houghton AM, Pierce RH, Gottardo R, Maloney DG, Riddell SR. Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade. Cancer Cell. 2021 Feb 8;39(2):193-208.e10. doi: 10.1016/j.ccell.2020.11.005. Epub 2020 Dec 24.

    PubMed 33357452

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Laboratory Biomarker Analysis and ROR1 CAR-specific Autologous T-Lymphocytes in people with Hematopoietic and Lymphoid Cell Neoplasm and Malignant Solid Neoplasm, run by Fred Hutchinson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 34 inclusion and 50 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 31 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 31 Aug 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants That Experienced Adverse Events (time frame: Within 35 days of receptor tyrosine kinase-like orphan receptor 1 positive chimeric antigen receptor-T cell infusion). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02706392, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Aug 2022.

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