Trial Title:
Study of CAR.70-engineered IL15-transduced Cord Blood-derived NK Cells in Conjunction With Lymphodepleting Chemotherapy for the Management of Advanced Renal Cell Carcinoma, Mesothelioma and Osteosarcoma
NCT ID:
NCT05703854
Condition:
Advanced Renal Cell Carcinoma
Advanced Mesothelioma
Advanced Osteosarcoma
Conditions: Official terms:
Carcinoma
Carcinoma, Renal Cell
Mesothelioma
Mesothelioma, Malignant
Osteosarcoma
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
CAR.70/IL15-transduced CB-derived NK cells
Description:
Given by IV (vein)
Arm group label:
Chemotherapy and NK Cell Infusion
Intervention type:
Drug
Intervention name:
Fludarabine phosphate
Description:
Given by IV (vein)
Arm group label:
Chemotherapy and NK Cell Infusion
Other name:
Fludarabine
Other name:
Fludara®
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Given by IV (vein)
Arm group label:
Chemotherapy and NK Cell Infusion
Other name:
Cytoxan®
Other name:
Neosar®
Summary:
To find a recommended dose of donated NK cells that can be given with lymphodepleting
chemotherapy to patients with advanced renal cell carcinoma, mesothelioma, or
osteosarcoma. The effects of this therapy will also be studied.
Detailed description:
Primary Objective:
- To determine the safety, tolerability, and optimal cell dose of chimeric antigen
receptor (CAR).70/interleukin (IL)15-transduced cord blood (CB)-derived natural
killer (NK) cells in patients with advanced renal cell carcinoma, advanced
mesothelioma, and advanced osteosarcoma.
- To determine the antitumor activity of CAR.70/IL15-transduced CB-derived NK cells.
Although the clinical benefit of CAR.70/IL15-transduced CB-derived NK cells has not
yet been established, the intent of offering this treatment is to provide a possible
therapeutic benefit and thus, the patient will be carefully monitored for tumor
response and symptom relief in addition to safety and tolerability. Efficacy will be
determined in each of the three cohorts.
Secondary Objectives:
- To quantify the persistence of infused allogeneic donor CAR-transduced CB-derived NK
cells in the recipient.
- To conduct comprehensive immune reconstitution studies.
- To obtain preliminary data on quality of life and patient experience.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Patients must meet the following criteria for study entry:
- Patients with advanced clear cell renal cell carcinoma, osteosarcoma or
mesothelioma, with an expression of CD70 in the pre-enrollment tumor sample ≥ 10%
measured by immunohistochemistry or flow cytometry for clear cell renal cell
carcinoma and mesothelioma, or ≥ 1% for osteosarcoma.
- Patients must meet disease-specific eligibility criteria (see below).
- Patients must be at least 2 weeks from last cytotoxic chemotherapy, tyrosine kinase
inhibitors or other targeted therapies at the time of administration of
lymphodepleting chemotherapy.
- Patients must be at least 3 months from any cell therapy for malignancy.
- Localized radiotherapy to 1 or more disease sites is allowed prior to the
lymphodepleting chemotherapy, provided that there are additional measurable
non-irradiated disease sites.
- Eastern Cooperative Oncology Group performance status 0 or 1 (Performance level as
measured by Karnofsky for patients > 16 years of age or Lansky for patients ≤ 16
years of age, see Appendix A).
- Adequate organ function at screening, as defined by the following:
1. Renal: Serum creatinine ≤ 1.5 mg/dL or estimated glomerular filtration rate
(Chronic Kidney Disease Epidemiology Collaboration equation) ≥30 ml/min/1.73 m2
2. Hepatic: alanine transaminase (ALT)/aspartate transaminase (AST) ≤ 2.5 x upper
limit of normal (ULN) or ≤ 5 x ULN if documented liver metastases, total
bilirubin ≤ 1.5 mg/dL or ≤ 3.0 mg/dL for patients with Gilbert's Syndrome. No
history of liver cirrhosis and no ascites.
3. Cardiac: Cardiac ejection fraction ≥ 50%, no clinically significant pericardial
effusion as determined by echocardiogram (ECHO) or multigated acquisition
(MUGA) scan, and no symptomatic cardiac disease or history of serious
ventricular arrhythmia (ie, ventricular tachycardia or ventricular
fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias
requiring anti-arrhythmic medications (except for atrial fibrillation that is
well controlled with anti-arrhythmic medication)
4. Pulmonary: No clinically significant pleural effusion (per principal
investigator [PI] judgement), and baseline oxygen saturation ≥ 92% on room air.
Subjects with active interstitial lung disease (ILD)/pneumonitis requiring
treatment with systemic steroids will be excluded.
5. Hematological: absolute neutrophil count (ANC) ≥ 1000/mm3, platelet count ≥
75,000/mm3, and hemoglobin ≥ 8 g/dL. For patients with human immunodeficiency
virus infection, CD4+ T-cell (CD4+) counts must be ≥ 350 cells/uL.
6. Coagulation: International normalized ratio (INR) ≤ 1.5 ULN and activated
partial thromboplastin time (aPTT) ≤ 1.5 ULN. Patients on therapeutic doses of
anticoagulation medication must have INR and/or aPTT ≤ the upper limit of the
therapeutic range for intended use.
- Able to provide written informed consent and if applicable pediatric assent.
- Aged 16-80 years.
- Weight ≥40 kg.
- All male and female patients who are able to have children must practice effective
birth control while on study therapy and for up to 3 months post completion of study
therapy. Acceptable forms of birth control for female patients include: hormonal
birth control, intrauterine device, diaphragm with spermicide, condom with
spermicide, or abstinence. Female patients who become pregnant or suspect pregnancy
must immediately notify their doctor. Females patients who become pregnant will be
taken off study. Men who are able to have children must use effective birth control
while on the study therapy. Acceptable forms of birth control for male patients
include: condom with spermicide or abstinence. If the male patient fathers a child
or suspects that he has fathered a child while on the study, he must immediately
notify his doctor.
- Negative serum or urine beta human chorionic gonadotropin pregnancy test for females
of childbearing potential (defined as not postmenopausal for 24 months or no
previous surgical sterilization or lactating females) at screening.
- Signed consent to long-term follow-up on protocol PA17-0483.
Disease-specific inclusion criteria
- Renal Cell Carcinoma
1. Patients must have a histologically confirmed diagnosis of Stage 4 RCC with a
clear cell component.
2. Patients must have received at least 1 prior line of therapy for recurrent or
metastatic disease, including both PD-1/programmed cell death-ligand 1
immunotherapy and anti-angiogenic-directed treatment, such as a tyrosine kinase
inhibitor. Prior progression on a PD-1 or PD-L1 checkpoint inhibitor should be
unequivocal.
3. Patients must have at least 1 measurable lesion >10 mm on computed tomography
(CT) per the RECIST v1.1.
- Mesothelioma
1. Patients must have pathologically confirmed mesothelioma
2. Patients must have progressive, recurrent, or refractory disease (local
recurrence) or new disease after all curative measures, including first-line
chemotherapy, targeted therapy, and radiotherapy. Prior progression on a PD-1
or PD-L1 checkpoint inhibitor should be unequivocal.
3. Patients must have measurable or evaluable disease per the RECIST v1.1 at
enrollment.
- Osteosarcoma
1. Patients must have histologically confirmed osteosarcoma that is recurrent or
refractory and for which standard curative measures do not exist or are no
longer effective. The patient must have received at least one chemotherapy
regimen based on anthracycline, if no contra-indication to this class of drug.
Must have histologic verification of their disease at diagnosis or at relapse.
2. Patients must have at least:
- Progressive, recurrent, or refractory disease (local recurrence) or new
disease after all curative measures, including first-line chemotherapy,
targeted therapy, and radiotherapy.
- Evidence of persistent and progressive disease on imaging, which may
include fludeoxyglucose F-18 positron emission tomography (PET)-avid
metastasis, that has failed to achieve CR to upfront conventional therapy
(surgery, chemotherapy), excluding lung metastases amenable to surgical
resection.
3. Patients must have evaluable or measurable disease per the RECIST v1.1 at
enrollment.
Exclusion Criteria:
Patients who meet any of the following criteria will be excluded from study entry:
- Presence of clinically significant ongoing Grade ≥ 2 toxicity unequivocally
associated with the previous anticancer treatment, as determined by the PI.
Toxicities related to prior surgery, radiation, prior systemic immune checkpoint
inhibitors and chemotherapy should be resolved to Grade 1 or below prior to
lymphodepletion.
- Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials
for management or not responding to appropriate therapy. Note: Patients with simple
urinary tract infection and uncomplicated bacterial pharyngitis are permitted if
responding to active treatment.
- Known active hepatitis B or C.
- Known human immunodeficiency virus with detectable viral load. Patients with
undetectable viral load may be excluded in case the antiretroviral drug cannot be
co-administered with the lymphodepleting chemotherapy and cannot be
changed/temporarily suspended, according to PI evaluation.
- Presence of active neurological disorder(s).
- Active autoimmune disease within 12 months of enrollment (excluding low-grade
psoriasis or well-controlled autoimmune thyroid disease).
- Amyloidosis or POEMS syndrome.
- Symptomatic or uncontrolled central nervous system involvement or signs of cord
compression. In the case radiation therapy is indicated, the washout must be at
least 14 days.
- Patients must not have any other malignancies within the past 2 years except for in
situ carcinoma of any site, adequately treated (without recurrence post resection or
post radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of
the skin, or active non-life-threatening second malignancy that would not, in the
investigator's opinion, potentially interfere with the patient's ability to
participate and/or complete this trial. Examples include but are not limited to:
urothelial cancer Grade Ta or T1 and adenocarcinoma of the prostate treated by
active surveillance.
- Presence of any other serious medical condition that may endanger the patient at
investigator's discretion, including but not limited to:
- New York Heart Association Class III or IV heart failure
- Myocardial infarction or stroke ≤ 26 weeks prior to CAR.70 NK cell infusion
- Unstable angina within ≤ 13 weeks prior to CAR.70 NK cell infusion unless the
underlying disease has been corrected by procedural intervention (e.g., stent,
bypass)
- Severe aortic stenosis
- Uncontrolled arrhythmia. PI approval is required for patients with arrhythmia
who may be included as an exception.
- Congenital long QT syndrome. PI approval is required.
- Documentation, during the screening process, of a QTc > 470 milliseconds by
Fredericia criteria (QTcF) based on the average of 3 electrocardiograms (ECGs)
taken approximately 1 minute apart and all within 10 minutes of each other. The
patient should be reclining for 5 minutes prior to ECGs. Local readings may be
used for this exclusion criterion.
- Major surgery < 4 weeks prior to first dose of lymphodepleting chemotherapy.
- Concomitant use of other investigational agents.
- Concomitant use of other anticancer agents.
- Previously received any anti-CD70 therapy.
- Patients receiving systemic steroid therapy at time of enrollment, with an exception
for topical, ocular, intranasal, and inhaled corticosteroids, or systemic
corticosteroids at an equivalent dose ≤ 10 mg of prednisone daily (physiological
substitutive doses are allowed).
- Received antithymocyte globulin within 14 days or Campath within 28 days of
enrollment.
- Patients receiving immunosuppressive therapy.
- Pregnant or breastfeeding.
Gender:
All
Minimum age:
16 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
M D Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
David Hong, MD
Phone:
713-563-5844
Email:
dshong@mdanderson.org
Investigator:
Last name:
David Hong, MD
Email:
Principal Investigator
Start date:
March 29, 2023
Completion date:
September 30, 2027
Lead sponsor:
Agency:
M.D. Anderson Cancer Center
Agency class:
Other
Source:
M.D. Anderson Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05703854
http://www.mdanderson.org
