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Cervical CancerPhase 1/2NCT01583686

CAR T Cell Receptor Immunotherapy Targeting Mesothelin for Patients With Metastatic Cancer

A Phase 1/2 study testing Fludarabine, Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) and Cyclophosphamide in people with Cervical Cancer and Pancreatic Cancer, run by National Cancer Institute (NCI) 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

Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with metastatic cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus… Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Cervical Cancer, Pancreatic Cancer, Ovarian Cancer
What is being tested?
Fludarabine, Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) and Cyclophosphamide
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
15 participants
Where
1 siteUnited States
Study dates
4 May 2012to 17 Dec 2018
Phase
Phase 1/2
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 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Metastatic or unresectable measurable cancers that express mesothelin. As in other protocols conducted by Dr. Hassan in the National Cancer Institute (NCI), epithelial mesotheliomas and pancreatic cancers do not need to be assessed for mesothelin expression since all of these tumors have been shown to express mesothelin. Other metastatic or unresectable cancers must be shown to expresses mesothelin as assessed by reverse transcription polymerase chain reaction (RT-PCR) or immunohistochemistry on tumor tissue. Bi-phasic mesotheliomas must express mesothelin on greater than 50% of the cells in the epithelial component. Diagnosis will be confirmed by the Laboratory of Pathology, NCI.
  • Patients must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic or unresectable disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.
  • Greater than or equal to 18 years of age and less than or equal to 70 years of age.
  • Willing to sign a durable power of attorney
  • Able to understand and sign the Informed Consent Document
  • Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
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  • Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.
  • Serology:
  • Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
  • Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be Hepatitis C virus ribonucleic acid (HCV RNA) negative.
  • Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  • Hematology:
  • Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim.
  • White blood cell (WBC) (> 3000/mm(3)).
  • Platelet count greater than 100,000/mm(3).
  • Hemoglobin greater than 8.0 g/dl.
  • Chemistry:
  • Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) less or equal to 2.5 times the upper limit of normal.
  • Serum creatinine less than or equal to 1.6 mg/dl.
  • Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
  • More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patient's toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
  • Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.
  • Subject's must be co-enrolled in protocol 03-C-0277.

Who cannot join

  • Patients with sarcomatoid mesothelioma as mesothelin is not expressed in this type of mesothelioma.
  • Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  • Patients with known brain metastases.
  • Patients receiving full dose anticoagulative therapy.
  • Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders or any other major medical illnesses.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
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  • Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
  • Patients with diabetic retinopathy.
  • Concurrent Systemic steroid therapy.
  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • History of coronary revascularization or ischemic symptoms.
  • Documented left ventricular ejection fraction (LVEF) of less than or equal to 45% tested in patients with:
  • Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second- or third-degree heart block, chest pain, or ischemic heart disease
  • Age greater than or equal to 65 years old
  • Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with:
  • A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).
  • Symptoms of respiratory dysfunction
  • Patients who are receiving any other investigational agents.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-mesothelin Gene Engineered Lymphocytes

Background:

The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with metastatic cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patients white blood cells with a retrovirus that has the gene for anti-mesothelin incorporated in the retrovirus.

Read more

Objective:

The purpose of this study is to determine a safe number of these cells to infuse and to see if these tumor fighting cells (anti-mesothelin cells) cause metastatic cancer tumors to shrink.

Eligibility:

  • Adults age 18-70 with metastatic cancer expressing the mesothelin molecule.

Design:

Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed

Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-mesothelin cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}

Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-mesothelin cells, and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.

Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.

Read the detailed description

Background:

  • We have constructed a single retroviral vector that contains a chimeric T cell receptor (CAR) that recognizes mesothelin, which can be used to mediate genetic transfer of this CAR with high efficiency (> 50%) without the need to perform any selection.
  • In co-cultures with mesothelin expressing cells, anti-mesothelin transduced T cells secreted significant amounts of interferon (IFN)-gamma with high specificity.

Objectives:

Primary Objectives:

  • To evaluate the safety of the administration of anti-mesothelin CAR engineered peripheral blood lymphocytes in patients receiving a non- myeloablative conditioning regimen, and aldesleukin.
  • Determine if the administration anti-mesothelin CAR engineered peripheral blood lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer.

Eligibility:

Patients who are 18 years of age or older must have

  • Metastatic or unresectable cancer that expresses mesothelin;
  • Previously received and have been a non-responder to or recurred after standard care;

Patients may not have:

-Contraindications for low dose aldesleukin administration.

Design:

  • Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be cultured in order to stimulate T-cell growth.
  • Transduction is initiated by exposure of approximately 10^8 to 5 X 10^8 cells to retroviral vector supernatant containing the anti-mesothelin CAR.
  • Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo CAR gene-transduced PBMC plus low dose intravenous (IV) aldesleukin
  • Patients will undergo complete evaluation of tumor with physical examination, Computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has stable disease (SD) or tumor shrinkage, repeat complete evaluations will be performed every 1-3 months. After the first year, patients continuing to respond will continue to be followed with this evaluation every 3-4 months until off study criteria are met.
  • The study will be conducted using a Phase I/II optimal design. The protocol will proceed in a phase 1 dose escalation design. Once the maximum tolerated dose (MTD) has been determined, the study then would proceed to the phase II portion. Patients will be entered into two cohorts based on histology: cohort 1 will include patients with mesothelioma, and cohort 2 will include patients with other types of cancer that express mesothelin.
  • For each of the 2 strata evaluated, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled in that stratum.
Being tested
Fludarabine, Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL), Cyclophosphamide, Aldesleukin
Keywords
Metastatic Cancer, Immunotherapy, Gene Therapy, Mesothelioma, Pancreatic Cancer
Medical subject headings
Uterine Cervical Neoplasms, Pancreatic Neoplasms, Ovarian Neoplasms, Mesothelioma, Lung Neoplasms, Neoplasm Metastasis

What participants receive

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

  • FludarabineDrug

    Also called Fludara

    Days -5 to Day -1: Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

  • Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL)Biological

    Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20 to 30 minutes.

  • CyclophosphamideDrug

    Also called Cytoxan

    Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml 5% dextrose in water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr.

  • AldesleukinDrug

    Also called Proleukin

    Aldesleukin 72,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Study groups in NCT01583686
Study groupRoleWhat they receive
1/Phase IExperimentalNon-myeloablative but lymphodepleting preparative regimen of cyclophosphamide and fludarabine plus anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) plus low dose aldesleukin.
Receives: Drug: Fludarabine; Biological: Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL); Drug: Cyclophosphamide; Drug: Aldesleukin
2/Phase IIExperimentalNon-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine + anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) + low-dose aldesleukin
Receives: Drug: Fludarabine; Biological: Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL); Drug: Cyclophosphamide; Drug: Aldesleukin

What is being measured

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

  1. Number of Patients With Objective Tumor Regression

    Objective tumor regression response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.0. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum LD. Progressive Disease (PD) is at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

    Measured: 3.5 mos.

  2. Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

    Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

    Measured: Date treatment consent signed to date off study, approximately 6 months and 17 days for Group A01, 16 months and 13 days for Group A02, 13 months and 3 days for Group A03, 10 months and 16 days for Group A04, and 11 months and 26 days for Group A05.

Timeline

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

  1. First posted24 Apr 2012 (estimated)
  2. Study start4 May 2012
  3. Primary completion17 Dec 2018
  4. Study completion17 Dec 2018

Why it stopped: Study terminated due to slow/insufficient accrual.

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 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01583686
Sponsor's protocol ID
120111
Other IDs
12-C-0111
Status last verified
Oct 2019
First submitted
20 Apr 2012
Last updated
14 Oct 2019
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 2007 Sep 1;13(17):5144-9. doi: 10.1158/1078-0432.CCR-07-0869.

    PubMed 17785569

  • Chang K, Pai LH, Pass H, Pogrebniak HW, Tsao MS, Pastan I, Willingham MC. Monoclonal antibody K1 reacts with epithelial mesothelioma but not with lung adenocarcinoma. Am J Surg Pathol. 1992 Mar;16(3):259-68. doi: 10.1097/00000478-199203000-00006.

    PubMed 1599018

  • Hassan R, Cohen SJ, Phillips M, Pastan I, Sharon E, Kelly RJ, Schweizer C, Weil S, Laheru D. Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin Cancer Res. 2010 Dec 15;16(24):6132-8. doi: 10.1158/1078-0432.CCR-10-2275. Epub 2010 Oct 29.

    PubMed 21037025

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Fludarabine, Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) and Cyclophosphamide in people with Cervical Cancer and Pancreatic Cancer, run by National Cancer Institute (NCI) 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 23 inclusion and 18 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 14 Oct 2019. 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 combined 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.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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 9 Oct 2019). 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 Patients With Objective Tumor Regression (time frame: 3.5 mos.). The study lists 2 primary outcomes in all. 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 NCT01583686, which also lists 3 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 14 Oct 2019.

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