Clinical trial NCT04231747: A Study of CC-97540, CD19-targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma
Official title: A Phase 1, Multicenter, Open-label Study of CC-97540, CD19-targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma Non-Hodgkin
Agressive Lymphoma
Diffuse-large B-cell Lymphoma (DLBCL)
Keywords: Lymphoma
B-cell non-Hodgkin lymphoma
Agressive Lymphoma
Diffuse-large B-cell Lymphoma
DLBCL
NHL
CC-97540
CD19
NEX-T chimeric antigen receptor (CAR) T cells
CAR-T
CART
Lead sponsor: Juno Therapeutics, a Subsidiary of Celgene
Sponsor class: INDUSTRY
First posted: 2020-01-18
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase 1, first-in-human, open-label, multicenter study of CC-97540, CD19-targeted NEX-T chimeric antigen receptor (CAR) T cells, in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma.

The study will consist of 2 parts: dose-escalation (Part A) and dose-expansion (Part B). The dose-escalation part (Part A) of the study is to evaluate the safety and tolerability of increasing dose levels of CC-97540 to establish a recommended Phase 2 dose (RP2D); and the dose-expansion part (Part B) of the study is to further evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of CC-97540 at the RP2D.


Eligibility criteria: Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Age ≥ 18 years at the time of informed consent.
2. Signed written informed consent obtained prior to any study procedure.
3. Willing and able to adhere to the study visit schedule and other protocol requirements.
4. Relapsed and/or refractory aggressive B-cell NHL as defined:

   1. Histologically confirmed DLBCL not otherwise specified, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (HGBCL), transformed DLBCL from follicular (tFL) or marginal zone lymphoma (tMZL), primary mediastinal B-cell lymphoma (PMBCL), or FL grade 3b (FL3B) (Note: Subjects with Richter's transformation (transformed DLBCL from CLL) are ineligible) AND
   2. Have relapsed and/or refractory disease after at least 2 lines of systemic therapy which must include at least one anthracycline and rituximab (or other anti-CD20 monoclonal antibody).

      Note: Lines of therapy will exclude those given for prior indolent lymphoma. It is not required for subjects to have had anthracycline for their DLBCL if received for indolent disease AND/OR
   3. Have relapsed and/or refractory DLBCL failed to ASCT treatment. Note: ASCT failure is defined as either failure to achieve an objective response (PR or better), or disease progression after ASCT(Note: Subjects who were not candidates to receive ASCT treatment (due to age or other factors) are eligible; the reason for not receiving ASCT must be documented in the electronic case report form (eCRF).
5. Positron emission tomography (PET)-positive disease as per the Lugano Classification (at screening or following bridging therapy, whichever is later).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Adequate organ function as detailed in the protocol.
8. Adequate vascular access for leukapheresis.
9. Willing and able to undergo tumor biopsies (in subjects with accessible disease).
10. Agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals as detailed in the protocol.
11. Female and male subjects agree to use effective contraception as detailed in the protocol.

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

1. Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or unwillingness or inability to follow the procedures required in the protocol.
2. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
3. Any condition that confounds the ability to interpret data from the study.
4. Central nervous system (CNS)-only involvement by malignancy (note: subjects with pathologically-confirmed secondary CNS involvement are allowed).)
5. Prior CAR T- cell or genetically-modified T- cell therapy, or prior CD19- targeted therapy (including, but not limited to, anti-CD19 mAbs or bispecific antibodies).)
6. Treatment with the following therapies or procedure within the specified period:

   1. Therapeutic doses of corticosteroids (defined as \> 20 mg/day prednisone or equivalent) within 14 days before leukapheresis administration. Physiologic replacement, topical, and inhaled steroids are permitted.
   2. Cytotoxic chemotherapeutic agents (eg, doxorubicin, vincristine, gemcitabine, oxaliplatin, carboplatin, etoposide) within 7 days of leukapheresis, with the exception of alkylating agents.
   3. Intrathecal therapy (eg, dexamethasone, methotrexate, cytosine arabinoside, cytarabine) within 7 days of leukapheresis.
   4. Oral chemotherapeutic agents, including lenalidomide and ibrutinib, are allowed if at least 5 half-lives have elapsed prior to leukapheresis.
   5. Alkylating agents (eg, cyclophosphamide, ifosfamide, bendamustine) within 4 weeks of leukapheresis.
   6. Any experimental therapy within 8 weeks (for biologics) or 5 half-lives (for small molecules) before leukapheresis
   7. Immunosuppressive therapies within 4 weeks of leukapheresis (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, immunosuppressive antibodies such as anti-TNF, anti-IL6, or anti-IL6R)
   8. Monoclonal antibodies (including rituximab, polatuzumab, etc.) within 7 days.
   9. Donor lymphocyte infusions within 6 weeks of leukapheresis
   10. Radiation within 6 weeks of leukapheresis. Subjects must have progressive disease in irradiated lesions or have additional non-irradiated, PET-positive lesions to be eligible. Radiation to a single lesion, if additional non-irradiated PET-positive lesions are present, is allowed up to 14 days prior to leukapheresis.
   11. Autologous stem-cell transplant (SCT) (ie, Day 0 receipt of hematopoietic stem cells) within 3 months of leukapheresis
   12. Washout of prior therapy (eg, bridging therapy for disease control)
7. Active autoimmune disease requiring immunosuppressive therapy.
8. Allogenic SCT (ie, Day 0 receipt of hematopoietic stem cells) within 6 months of leukapheresis or presence of ongoing symptoms or treatment for chronic graft-versus host disease (GVHD).)
9. Hypersensitivity to fludarabine and/or cyclophosphamide.
10. Prior history of malignancies, other than studied NHL, unless the subject has been free of the disease for ≥ 2 years except for the following non-invasive malignancies:

    1. Basal or squamous cell carcinoma of the skin
    2. Carcinoma in situ of the cervix or the breast
    3. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM (tumor, nodes, metastasis) clinical staging system) or prostate cancer that is curative
    4. Other completely resected stage 1 solid tumor with low risk for recurrence
11. Active hepatitis B, hepatitis C, or any human immunodeficiency virus (HIV) infection at the time of screening.
12. Uncontrolled or active systemic fungal, bacterial, viral or other infection despite appropriate anti-infection treatment at the time of leukapheresis or pre-treatment evaluation.
13. History of any one of the following cardiovascular conditions within the 6 months prior to screening: Class III or IV heart failure as defined by the New York Heart Association, myocardial infarction, unstable angina, angioplasty or stenting, or other clinically significant cardiac disease.
14. History or presence of clinically significant CNS pathology such as seizure disorder, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, or cerebellar disease. Presence of clinically active psychosis.
15. History of ≥ Grade 2 hemorrhage within 30 days of screening.
16. Pregnant or nursing (lactating) women.
17. Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to leukapheresis or initiation of LD chemotherapy.

    -Acute symptoms must have resolved and based on investigator assessment in consultation with the Sponsor Medical Monitor, there are no sequelae that would place the subject at a higher risk of receiving study treatment.
18. Previous SARS-CoV-2 vaccine within 14 days prior to leukapheresis or initiation of LD chemotherapy.

Primary outcomes:
measure: Adverse Events (AEs)
timeFrame: From the time of informed consent and follow up to 2 years after infusion of CC-97540
Secondary outcomes:
measure: Complete Response Rate (CRR)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Overall response Rate (ORR)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Duration of response (DOR)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Time to response (TTR)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Time to complete response (TTCR)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Progression free survival (PFS)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Overall survival (OS)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Pharmacokinetics - peak expansion (Cmax)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Pharmacokinetics -time to peak expansion (tmax)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Pharmacokinetics - elimination half-life (t1/2)
timeFrame: Up to 2 years after CC-97540 infusion
measure: Pharmacokinetics - Area under curve (AUC)
timeFrame: Up to 2 years after CC-97540 infusion
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Local Institution - 003
state: Alabama
city: Atlanta
country: United States
facility: Local Institution - 004
state: Georgia
city: Boston
country: United States
facility: Local Institution - 011
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Omaha
country: United States
facility: Nebraska Medicine Fred and Pamela Buffett Cancer Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Local Institution - 001
state: New York
city: New York
country: United States
facility: Local Institution - 008
state: New York
city: Charlotte
country: United States
facility: Local Institution - 010
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University OHSU
state: Oregon
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute - University of Utah
state: Utah
city: Calgary
country: Canada
facility: Foothills Medical Centre - Tom Baker Cancer Centre
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.