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TerminatedPhase 1ACTRN12622001542785

A pilot study of Lewis-Y targeting Chimeric Antigen Receptor T-cells given in combination with Nivolumab in Lewis-Y expressing solid tumours.

A Pilot Study Assessing Safety and Tolerability of Lewis Y (LeY) targeting Chimeric Antigen Receptor (CAR) T cells in combination with Nivolumab in Patients With LeY Expressing Solid Tumours

Sponsor

Peter MacCallum Cancer Centre

Enrollment

18 participants

Start Date

Jan 17, 2023

Study Type

Interventional

Conditions

LeY Expressing Advanced Solid Tumours

Summary

The main purpose of this study is to test the safety of a new cancer therapy targeting the tumour marker Lewis Y (‘Lewis Y Chimeric Antigen Receptor T-cell Therapy’) in combination with the commonly used cancer drug nivolumab for the treatment of patients with Lewis Y-expressing solid tumours. Who is it for? You may be eligible to join this study if you are aged 18 years or older, you have an advanced incurable or metastatic cancer and your cancer expresses the marker Lewis Y on tumour biopsy. Study details All participants will receive treatment with Lewis Y Chimeric Antigen Receptor T-cell Therapy and nivolumab. Prior to treatment, participants will have blood collected to generate the T-cells required for treatment. Participants will then follow a chemotherapy regimen designed to reduce the number of the body’s T cells so that the newly generated T-cells can be administered. This will involve intravenous infusions of the drugs fludarabine and cyclophosphamide once per day for 3 consecutive days in the week prior to T-cell therapy. Patients enrolled in this study will be part of one of two groups of patients: -Dose escalation for LeY CAR T cells with nivolumab -Dose expansion for LeY CAR T cells with nivolumab The dose escalation phase is when different doses (total number of cells infused) of the cell therapy will be tested. Each participant will receive one dose only by intravenous infusion. The doses tested will be increased or decreased for additional participants enrolled until a safe dose is determined. This safe dose will then be used for the dose expansion phase, where participants may receive up to two doses of cells infused one hour apart by intravenous infusion. Nivolumab will be administered to all participants by intravenous infusion on the day prior to T-cell therapy, and on days 14, 28, and 42 after T-cell therapy. During the follow-up phase, beyond the first 8 weeks (day 56) post-infusion, imaging and blood tests will occur once a month up to one year post-infusion then every 3 months thereafter for long-term follow-up to the full study period of 5 years. It is hoped that Lewis Y Chimeric Antigen Receptor T-cell therapy in combination with nivolumab is safe, tolerable, and effective for the treatment of advanced solid cancers expressing the Lewis Y marker. This study will also help to define the dose of T-cell therapy that may be used for treatment of similar individuals in future.

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria31

  • Patient has provided written confirmation of informed consent on participant information and consent form (PICF)
  • Patients with an advanced solid tumour (defined as incurable locally advanced or metastatic disease and excluding any haematologic malignancy) Patients who are eligible for PBS-reimbursed PD1 or PD-L1 inhibitors must have received this prior to study enrolment
  • Tumour is positive for LeY expression by immunohistochemistry (IHC) defined as a staining of greater than or equal to 10 % of tumour cells positive for LeY expression
  • Patient is at least 18 years of age at the time of consent
  • Patient has an ECOG performance status of 0-1
  • Life expectancy of greater or equal to 12 weeks
  • Patient has adequate organ function satisfying all of the following:
  • Bilirubin less than or equal to 1.5x upper limit of normal (ULN) unless patient has known Gilbert’s syndrome, then less than or equal to 3x ULN
  • AST/ALT less than or equal to2.5 x ULN except in patients with known liver metastases where AST/ALT less than or equal to 5.0 x ULN
  • Serum creatinine less than 1.5x ULN or creatinine clearance greater than 50ml/min. Creatinine clearance is either derived using the Cockcroft-Gault formula or may be measured by 24 hour urine collection or nuclear medicine assessment
  • Adequate pulmonary function defined by SaO2 greater than 91% on room air and less than or equal to grade I dyspnoea
  • Left ventricular ejection fraction (LVEF) greater than or equal to 40% as confirmed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA)
  • Absolute neutrophil count (ANC) greater than or equal to 1.0 x 10^(9)/L
  • Absolute lymphocyte count greater than or equal to 0.5 x 10^(9)/L
  • Platelets greater than or equal to 100 x 10^(9)/L
  • Haemoglobin greater than or equal to 80g/L
  • White cell count (WCC) less than 30 x 10^(9)/L
  • Patient is deemed capable and willing to undergo the planned study procedures in the view of the Investigator
  • Patient has measurable disease as per RECIST 1.1
  • For patients undergoing the (64)^Cu SPION imaging:
  • a. Patient must pass institutional MRI safety questionnaire
  • b. Patient must not exceed physical limitations of scanner (weight greater than 105kg and/or height greater than 185cm)
  • c. Patient must feel they are able to tolerate proposed imaging sequences (e.g. Patient must not suffer from severe claustrophobia or other condition that would prevent them from undergoing MRI)
  • d. Patients must not have a known allergy to nickel or palladium
  • Female patients of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female patients of childbearing potential must be willing to commit to either abstaining continuously from heterosexual intercourse or agree to practice 2 methods of reliable birth control simultaneously. Where one of the methods is a highly effective method of contraception (failure rate of less than 1% per year when used consistently and correctly; see examples below) and one other effective method (i.e., male latex or synthetic condom, diaphragm, or cervical cap) and patient must agree to remain on both methods from the time of signing the patient information and consent form (PICF) until at least 1 year after receiving LeY CAR T cell therapy. Reliable contraception is indicated even where there has been a history of infertility, unless it is due to hysterectomy. Women of childbearing potential (WOCBP) should be referred to a qualified provider of contraceptive methods, if needed. Examples of highly effective contraceptives include:
  • User-independent methods: 1) implantable progestogen-only hormone contraception associated with inhibition of ovulation; 2) intrauterine device; intrauterine hormone-releasing system; 3) vasectomised partner
  • User-dependent method: progestogen-only hormone contraception associated with inhibition of ovulation (oral or injectable)
  • Woman of childbearing potential are those who have not been surgically sterilized or have not been free from menses related to menopause for greater than 1 year
  • Male patients must commit either to abstaining continuously from heterosexual intercourse or a man who is sexually active with a woman of childbearing potential or a pregnant woman must agree to use a barrier method of contraception from the time of
  • signing the PICF until at least 1 year after receiving LeY CAR T cell therapy, even if they have undergone a successful vasectomy

Exclusion Criteria18

  • Patients with known active central nervous system (CNS), involvement by malignancy. [N.B. Patients with previously treated and/or neurologically stable disease (asymptomatic brain metastases not requiring steroid treatment) will be eligible]
  • Prior CAR T cell therapy
  • Patient has been given chemotherapy and/or granulocyte-colony stimulating factor (G-CSF) within 4 weeks of study registration or is planned to receive such therapy prior to apheresis of PBMC. Patients can only receive cytotoxic drugs as per the schedule of treatment for this protocol
  • Patient has had immunosuppressive therapy within 4 weeks of apheresis. Therapeutic doses of steroids (defined as greater than 10 mg/day of Prednisolone (or equivalent)) must be able to be stopped within 7 days prior to leukapheresis and 72 hours prior to LeY CAR T cell infusion. Physiologic doses of steroid (e.g. Prednisolone less than 10mg or equivalent), topical and inhaled steroids are permitted
  • Patients who are eligible for potentially curative therapy
  • Uncontrolled active or latent Hepatitis B (HBV) or active Hepatitis C (HCV) or HIV
  • Patients with uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate treatment
  • A presence of active clinically relevant CNS pathology such as epilepsy, aphasia, severe brain injury, dementia, Parkinson’s disease, cerebellar disease or psychosis
  • Radiation therapy within 2 weeks prior to registration
  • Patient has an active other haematologic or solid malignancy with the exception of superficial BCC or SCC
  • Patient has a history of significant pulmonary disease (including radiation pneumonitis) or known, biopsy proven autoimmune inflammatory disease of the gastrointestinal tract
  • Unstable angina or myocardial infarct within 6 months prior to screening
  • Patient has known clinically significant autoimmune disease
  • Women who are pregnant or breastfeeding
  • Patient has a serious uncontrolled medical disorder, psychological or social factors that which would impair their ability to receive protocol therapy and follow up in the opinion of the investigator
  • Receipt of live attenuated vaccination within 30 days of registration
  • Prior allogeneic organ transplant, inflammatory bowel disease, pneumonitis, tuberculosis, or primary immunodeficiency
  • Have a history of allergy to study drug components, or a history of severe hypersensitivity reaction to any mAb

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Interventions

This is a pilot, single-centre, dose escalation with dose expansion study designed to investigate the safety and tolerability of a single infusion of LeY CAR T cells in combination with nivolumab in p

This is a pilot, single-centre, dose escalation with dose expansion study designed to investigate the safety and tolerability of a single infusion of LeY CAR T cells in combination with nivolumab in patients with LeY positive advanced solid tumours. To ensure a sufficient yield of T-lymphocytes, patients are to undergo a steady-state apheresis of mononuclear cells (MNC) without influence of recent chemotherapy or growth factors. For the MNC collection an initial apheresis cycle is to be performed to obtain sufficient quantity of cells to generate LeY CAR T cells. This procedure could last approximately 2-4 hours. It is possible that additional apheresis procedures are needed, such as if there are technical issues or if the procedure needs to be stopped early for some reason. The expected yield of cells will be total nucleated cells 2-7 X10^(9) per patient. These cells will be stored in vapour phase liquid nitrogen for subsequent use. To increase immunosuppression and improve persistence of engineered T-cells, patients will receive a lymphodepleting conditioning chemotherapy regimen before re-infusion of the transduced T-cells. Lymphodepleting conditioning chemotherapy should be initiated so as to finish at least 48 hours prior to LeY CAR T cells administration. Patients will receive intravenous lymphodepleting conditioning chemotherapy regimen for 3 consecutive days prior to LeY CAR T cell infusion. The lymphodepleting conditioning chemotherapy should be started within 7 days prior to re-infusion of the LeY CAR T cells and must be completed at least 48 hours before the re-infusion of the LeY CAR T cells. The lymphodepleting conditioning chemotherapy regimen is as follows: -Fludarabine (25 mg/m^(2) per day) and -Cyclophosphamide (300mg/m^(2) per day) Both are to be administrated for 3 consecutive days prior to LeY CAR T cell infusion. Nivolumab is to be administered as a 30-minute intravenous infusion, on day -1 (the day prior to LeY CAR T cell infusion), day 14, 28 and 42. There are 3 planned dose levels of LeY CAR T cell that will be evaluated in conjunction with 240 mg of Nivolumab. LeY CAR T cell dose escalation/de-escalation decisions will be made by the data safety monitoring committee (DSMC). The first dose to be evaluated will be dose level D1 (2 x10^(8) plus up to 6 x 10^(7) labelled cells) and dose escalation will follow a Bayesian Optimal Interval (BOIN) study design to find the MTD for LeY CAR T cells with nivolumab. After each cohort completes the dose limiting toxicity (DLT) observation period, the DSMC will meet and review the available toxicity and dosing information and determine the next dose level for the following cohort of patients and/or identify the recommended phase II dose for the dose-expansion phase. LeY CAR T Cell Dose Escalation as follows: Dose level - 1: 1 x10^(8) plus up to 3 x 10^(7) labelled cells Dose level 1: 2 x10^(8) plus up to 6 x 10^(7) labelled cells Dose level 2: 5 x10^(8) plus up to 1.5 x 10^(8) labelled cells Dose level 3: 1 x10^(9) plus up to 3 x 10^(8) labelled cells The first dose to be evaluated will be dose level D1 and dose escalation will follow a Bayesian Optimal Interval (BOIN) study design to find the maximum tolerated dose (MTD) for LeY CAR T cells with nivolumab. The BOIN design is a novel Bayesian dose-finding method that optimizes patient treatment ethics by minimizing the chance of exposing patients to sub-therapeutic and overly toxic doses as well accelerating the rate of reaching the MTD. The BOIN design is implemented in a simple way similar to the traditional “3+3” design but is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model-based designs. Dose escalation/de-escalation decisions will be made by the DSMC. The target toxicity rate for the MTD is 0.3 and the maximum sample size is 18. Initially there will be accelerated dose escalation with cohorts of 1 patient. Finally, we will enroll and treat patients in cohorts of size 3. To guide dose-escalation decisions: 1) if the observed DLT rate at the current dose is less than or equal to 0.236, the next cohort of patients will be treated at the next higher dose level 2) if the observed DLT rate at the current dose is is less than or equal to 0.359, the next cohort of patients will be treated at the next lower dose level. When the lowest dose is eliminated, stop the trial for safety. Patients in the expansion phase will be separate to those enrolled in the dose escalation phase. Participants cannot be enrolled in both phases. All patients in the dose escalation phase will receive one dose of LeY CAR T cells which will be administered (Day 0) via an intravenous infusion given approximately over 30 minutes. Additionally, patients enrolled in the expansion phase of the study, will receive two administrations of LeY CAR T cells. The first dose of LeY CAR T cells will be unlabelled cells and a second intravenous dose of 64Cu-nanoparticle labelled LeY CAR T, approximately 1 hour following the initial LeY CAR T cell infusion. In patients given 64Cu-nanoparticle labelled LeY CAR T cells, a minimum of 10% and a maximum of 30% of the total number of LeY CAR T cells infused will be labelled with the 64Cu nanoparticle. Cells will be labelled with a maximum of 700MBq per patient. The purpose of this markers is to provide a way of tracking T cells in the body. Once the MTD is defined in the dose escalation phase, if 18 patients have not received LeY CAR T cells with nivolumab, further recruitment will occur. If 12 patients were treated at the MTD dose in this escalation phase, up to an additional 6 evaluable patients will be accrued to this dose expansion phase for a total of up to 18 patients in both escalation and expansion phases of study of LeY CAR T cells and nivolumab. Data will be collected using electronic case report forms - eCRFs. The site PI is required to prepare and maintain adequate and accurate medical records designed to record all observations and other data pertinent to the trial for each trial patient. The medical records must contain adequate information to allow for verification of patient identity throughout the trial. Source data must be attributable, legible, contemporaneous, complete, consistent, original and accurate. De-identified copies of data relating to primary end-points and safety (i.e. AEs logs) must be provided to BaCT in accordance with the Site Source Data Verification Checklist for this trial.

Locations(1)

Peter MacCallum Cancer Centre - Melbourne

VIC, Australia

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ACTRN12622001542785