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

Sponsor

Juno Therapeutics, a Subsidiary of Celgene (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04231747

Collaborator

(none)

Enrollment

Locations

Arm

56.3

Anticipated Duration (Months)

4.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma Non-Hodgkin Agressive Lymphoma Diffuse-large B-cell Lymphoma (DLBCL)	Biological: CC-97540	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 22, 2020

Anticipated Primary Completion Date :

Jan 31, 2025

Anticipated Study Completion Date :

Jan 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CC-97540 monotherapy Subjects will be assigned to receive CC-97540 followed by 3 consecutive doses of lymphodepleting chemotherapy (fludarabine IV (30 mg/m2/day) and cyclophosphamide IV (300 mg/m2/day).	Biological: CC-97540 Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to produce CC 97540. During CC 97540 production, subjects may receive bridging chemotherapy for disease control. Upon successful generation of CC 97540 product, subjects will receive treatment with CC 97540 therapy. Each cycle will include lymphodepleting chemotherapy followed by one dose of CC 97540 administered by intravenous (IV) injection.

Arm

Intervention/Treatment

Experimental: CC-97540 monotherapy

Subjects will be assigned to receive CC-97540 followed by 3 consecutive doses of lymphodepleting chemotherapy (fludarabine IV (30 mg/m2/day) and cyclophosphamide IV (300 mg/m2/day).

Biological: CC-97540

Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to produce CC 97540. During CC 97540 production, subjects may receive bridging chemotherapy for disease control. Upon successful generation of CC 97540 product, subjects will receive treatment with CC 97540 therapy. Each cycle will include lymphodepleting chemotherapy followed by one dose of CC 97540 administered by intravenous (IV) injection.

Outcome Measures

Primary Outcome Measures

Adverse Events (AEs) [From the time of informed consent and follow up to 2 years after infusion of CC-97540]
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE.ject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the sub

Secondary Outcome Measures

Complete Response Rate (CRR) [Up to 2 years after CC-97540 infusion]
The proportion of subjects with a best overall response of complete response (CR).
Overall response Rate (ORR) [Up to 2 years after CC-97540 infusion]
The proportion of subjects achieving CR or partial response (PR).
Duration of response (DOR) [Up to 2 years after CC-97540 infusion]
The time from first response to progressive disease (PD) or death.
Time to response (TTR) [Up to 2 years after CC-97540 infusion]
Time from CC-97540 infusion to the first documentation of response (CR or PR).
Time to complete response (TTCR) [Up to 2 years after CC-97540 infusion]
Time from CC-97540 infusion to the first documentation of CR
Progression free survival (PFS) [Up to 2 years after CC-97540 infusion]
Time from CC-97540 infusion to the first documentation of PD, or death from any cause, whichever occurs first
Overall survival (OS) [Up to 2 years after CC-97540 infusion]
Time from CC-97540 infusion to death
Pharmacokinetics - peak expansion (Cmax) [Up to 2 years after CC-97540 infusion]
Maximum blood concentration
Pharmacokinetics -time to peak expansion (tmax) [Up to 2 years after CC-97540 infusion]
Time to peak (maximum) blood concentration
Pharmacokinetics - elimination half-life (t1/2) [Up to 2 years after CC-97540 infusion]
Elimination half-life
Pharmacokinetics - Area under curve (AUC) [Up to 2 years after CC-97540 infusion]
Area under the curve

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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

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).
Positron emission tomography (PET)-positive disease as per the Lugano Classification (at screening or following bridging therapy, whichever is later).
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Adequate organ function as detailed in the protocol.
Adequate vascular access for leukapheresis.
Willing and able to undergo tumor biopsies (in subjects with accessible disease).
Agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals as detailed in the protocol.
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:

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.
Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
Any condition that confounds the ability to interpret data from the study.
Central nervous system (CNS)-only involvement by malignancy (note: subjects with pathologically-confirmed secondary CNS involvement are allowed).)
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).)
Treatment with the following therapies or procedure within the specified period:
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.
Cytotoxic chemotherapeutic agents (eg, doxorubicin, vincristine, gemcitabine, oxaliplatin, carboplatin, etoposide) within 7 days of leukapheresis, with the exception of alkylating agents.
Intrathecal therapy (eg, dexamethasone, methotrexate, cytosine arabinoside, cytarabine) within 7 days of leukapheresis.
Oral chemotherapeutic agents, including lenalidomide and ibrutinib, are allowed if at least 5 half-lives have elapsed prior to leukapheresis.
Alkylating agents (eg, cyclophosphamide, ifosfamide, bendamustine) within 4 weeks of leukapheresis.
Any experimental therapy within 8 weeks (for biologics) or 5 half-lives (for small molecules) before leukapheresis
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)
Monoclonal antibodies (including rituximab, polatuzumab, etc.) within 7 days.
Donor lymphocyte infusions within 6 weeks of leukapheresis
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.
Autologous stem-cell transplant (SCT) (ie, Day 0 receipt of hematopoietic stem cells) within 3 months of leukapheresis
Washout of prior therapy (eg, bridging therapy for disease control)
Active autoimmune disease requiring immunosuppressive therapy.
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).)
Hypersensitivity to fludarabine and/or cyclophosphamide.
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:
Basal or squamous cell carcinoma of the skin
Carcinoma in situ of the cervix or the breast
Incidental histologic finding of prostate cancer (T1a or T1b using the TNM (tumor, nodes, metastasis) clinical staging system) or prostate cancer that is curative
Other completely resected stage 1 solid tumor with low risk for recurrence
Active hepatitis B, hepatitis C, or any human immunodeficiency virus (HIV) infection at the time of screening.
Uncontrolled or active systemic fungal, bacterial, viral or other infection despite appropriate anti-infection treatment at the time of leukapheresis or pre-treatment evaluation.
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.
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.
History of ≥ Grade 2 hemorrhage within 30 days of screening.
Pregnant or nursing (lactating) women.
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.

Previous SARS-CoV-2 vaccine within 14 days prior to leukapheresis or initiation of LD chemotherapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294
2	Northside Hospital - Blood and Bone Marrow Transplant Group of Georgia	Atlanta	Georgia	United States	30342
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
5	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
6	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
7	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
8	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
9	Weill Cornell Medicine	New York	New York	United States	10065
10	Levine Cancer Institute	Charlotte	North Carolina	United States	28207
11	Oregon Health & Science University (OHSU)	Portland	Oregon	United States	97239
12	Oregon Health and Science University OHSU	Portland	Oregon	United States	97239
13	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
14	Local Institution - 020	Calgary	Alberta	Canada	T2N 2T9
15	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4Z6
16	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
17	Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 1C3