A Safety and Efficacy Trial of JCAR017 Combinations in Subjects With Relapsed/Refractory B-cell Malignancies

Lymphoma, Non-Hodgkin Clinical Trial

— PLATFORM  

Official title:

An Exploratory Phase 1/2 Trial To Evaluate The Safety And Efficacy Of JCAR017 Combinations In Subjects With Relapsed/Refractory B-Cell Malignancies (PLATFORM)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03310619
• Other study ID #: JCAR017-BCM-002
• Secondary ID: U1111-1201-2046
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 20, 2017
• Est. completion date: February 15, 2023

Study information

• Verified date: March 2024
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a global, open-label, multi-arm, parallel multi-cohort, multi-center, Phase 1/2 study to determine the safety, tolerability, PK, efficacy and patient-reported quality of life of JCAR017 in combination with various agents. This protocol is intended to evaluate various drug combinations with JCAR017, as separate arms, over the life of the protocol, using the same objectives. Each combination will be evaluated separately (ie, the intention is not to compare between combinations) for the purposes of the objectives, trial design, and statistical analysis. The following combinations will be tested: Arm A: JCAR017 in combination with durvalumab Arm B: JCAR017 in combination with CC-122 (avadomide) Arm C: JCAR017 in combination with CC-220 (iberdomide) Arm D: JCAR017 in combination with ibrutinib Arm E: JCAR017 in combination with relatlimab and/or nivolumab Arm F: JCAR017 in combination with CC-99282 Additional arms will be added by way of amendment once combination agents have been selected. The study will consist of 2 parts: dose finding (Phase 1) and dose expansion (Phase 2). Dose expansion may occur in one or more arms.

Description:

During Phase 1, different arms may be opened to test JCAR017 in combination with combination agent(s) in adult subjects with R/R aggressive B-cell NHL. Within each arm, different doses and schedules of JCAR017 and the combination agent(s) may be tested in several cohorts and subcohorts per arm. During Phase 2 of the study, the expansion of any dose level and schedule for any arm that has been shown to be safe may occur. Arm A will test JCAR017 in combination with Durvalumab Arm B will test JCAR017 in combination with CC-122 Arm C will test JCAR017 in combination with CC-220 (iberdomide ) Arm D will test JCAR017 in combination with ibrutinib. Arm E will test JCAR017 in combination with relatlimab and/or nivolumab Arm F will test JCAR017 in combination with CC-99282 All subjects from Phase 1 and Phase 2 will be followed for 24 months following JCAR017 infusion. Post-study follow-up for survival, relapse, long-term toxicity (including new malignancies), and viral vector safety will continue under a separate long-term follow-up (LTFU) protocol for up to 15 years after the JCAR017 dose as per health authority regulatory guidelines.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: February 15, 2023
• Est. primary completion date: February 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subject is = 18 years of age at the time of signing the informed consent form ().

2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.

3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

4. Subject must have aggressive B-cell NHL according to "the 2016 revision of the WHO classification of lymphoid neoplasms", histologically confirmed at last relapse by the

treating institution, defined as:

1. Diffuse large B-cell lymphoma (DLBCL) Not otherwise specified (NOS) including transformed indolent Non-Hodgkin lymphoma (NHL)

2. Follicular lymphoma Grade 3B

3. T cell/histiocyte-rich large B-cell lymphoma

4. Epstein-Barr virus (EBV) positive DLBCL, NOS

5. Primary mediastinal (thymic) large B-cell lymphoma

6. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma)

5. Subjects disease must have relapsed or be refractory to at least 2 prior lines of therapy. Previous therapy must have included a CD20-targeted agent and an anthracycline.

6. Subject must have

1. Positron emission tomography (PET)-positive (Deauville score 4 or 5) and computed tomography (CT) measurable disease as per Lugano Classification

2. Sum of product of perpendicular diameters (SPD) of up to 6 index lesions = 25 cm2 by CT scan (not applicable to Arm A or B or subjects with Richter's transformation)

7. Eastern Cooperative Oncology Group (ECOG) performance status = 1 at screening

8. Adequate organ function

9. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals

10. Participants must agree to use effective contraception

Exclusion Criteria:

1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study based on investigator´s judgment.

2. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study based on investigator´s judgment.

3. Subject has any condition that confounds the ability to interpret data from the study based on investigator´s judgment.

4. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been free of the disease for = 2 years with the exception of the following

non-invasive malignancies:

1. Basal cell carcinoma of the skin

2. Squamous cell carcinoma of the skin

3. Carcinoma in situ of the cervix

4. Carcinoma in situ of the breast

5. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative.

6. Other completely resected stage 1 solid tumor with low risk for recurrence

5. Prior treatment with any prior gene therap y product

6. Prior treatment with any adoptive T cell therapy; prior hematopoietic stem cell transplant (HSCT) is allowed

7. Allogeneic HSCT within 90 days of leukapheresis

8. Prior treatment with the combination agent from the assigned arm:

1. Anti PD-1 or PD-L1 (Arm A and E)

2. CC-122 (Arm B)

3. CC-220 (Arm C)

4. Prior treatment with ibrutinib is not exclusionary for subjects on any study arm

5. Anti LAG-3 targeted agent (Arm E)

6. CC-99282 (Arm F)

9. Presence of acute or chronic graft-versus-host disease (GVHD)

10. Presence of the following:

1. Active hepatitis B or active hepatitis C infection

2. History of or active human immunodeficiency virus (HIV) infection

11. Uncontrolled bacterial, viral or fungal infection at the time of leukapheresis, lymphodepleting chemotherapy or JCAR017 infusion

12. Any history of myocarditis (Arm E); history of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease (all arms)

13. History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis

14. Subjects with active CNS or cerebrospinal fluid (CSF) involvement by malignancy

15. Pregnant or nursing (lactating) women.

16. Subjects with active auto immune disorders/processes or active neurological or inflammatory disorders

17. For subjects to receive oral combination therapy (Arms B, C, D or F): History of a gastrointestinal (GI) condition or procedure that in the opinion of the investigator may affect oral drug absorption.

18. Progressive tumor invasion of venous or arterial vessels.

19. Deep venous thrombosis (DVT)/pulmonary embolism (PE) not managed on a stable regimen of anticoagulation.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Follicular
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Non-Hodgkin
• Neoplasms

Intervention

Biological:
• JCAR017
Gene modified autologous T cells

Drug:
• Durvalumab
Anti-PD-L1
• CC-122
Pleiotropic Pathway Modifier
• Ibrutinib
Ibrutinib
• CC-220
CC-220
• Relatlimab
Relatlimab
• Nivolumab
Nivolumab
• CC-99282
CC-99282

Locations

Country	Name	City	State
United States	Local Institution - 022	Atlanta	Georgia
United States	Local Institution - 012	Boston	Massachusetts
United States	Local Institution - 021	Boston	Massachusetts
United States	Local Institution - 014	Chicago	Illinois
United States	Local Institution - 011	Duarte	California
United States	Local Institution - 013	Houston	Texas
United States	Local Institution - 015	Omaha	Nebraska
United States	Local Institution - 016	Philadelphia	Pennsylvania
United States	Local Institution - 020	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose-Limiting Toxicity (DLT)	Participants enrolled in Phase 1 are considered evaluable for DLTs if they received an infusion of conforming JCAR017 cell product and at least one dose of the combination agent and completed the specified DLT evaluation period or if they have received an infusion of conforming JCAR017 cell product and at least one dose of the combination agent and experience a DLT during the DLT evaluation period.	From first dose of the combination agent until 1 month (28 days) after JCAR017 infusion (pre- JCAR017 cohort) or from JCAR017 infusion until 1 month (28 days) after the first dose of combination agent (post-JCAR017 cohort)
Primary	Complete Response Rate (CRR)	Percentage of participants achieving a complete response (CR). CR is complete radiologic response (CRR) and complete metabolic response (CMR). CR was measured using CT and PET and assessed for the presence of index and non-index lesions, spleen size, and the absence of new lesions or diseased bone marrow.; To be considered as having CRR participants had to have all of the following: Index lesions - longest transverse diameter of nodal lesions = 1.5 cm and the absence of extranodal disease.; Non-index lesions - the absence of non-index lesions.; Spleen size <13 cm; The absence of new lesions; Normal bone marrow assessment; To be considered as having CMR participants had to have all of the following: A score of 1, 2, or 3 with or without residual mass on 5-PS for index and non-index lesions.; The absence of new lesions; No evidence of FDG-avid disease in marrow and a normal bone marrow assessment	At 3 and 6 months post-JCAR017 infusion.
Secondary	European Organisation for Research and Treatment of Cancer - Quality of Life C30 Questionnaire (EORTC QLQ-C30) Scores - Phase 2	The EORTC QLQ-C30 is composed of five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/health-related quality of life (HRQoL) scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The questionnaire is scored on a 4-point Likert response scale: 1 = not at all, 2 = a little, 3 = quite a bit, and 4 = very much.; The raw score is calculated as the average of the items that contribute to the scale. The final scores are calculated via linear transformation of raw scores and range from 0 to 100.; For functional scales (physical, role, emotional, social, cognitive and global health) higher scores indicate better QoL.; For symptom scales (fatigue, nausea and vomiting and pain) and single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) lower scores indicate fewer symptoms, i.e. better QoL.	At baseline and 29 days and 57 days post JCAR017 dose
Secondary	EuroQol- 5 Dimensions of Health Visual Analogue Scale (EQ-5D VAS) Scores - Phase 2	The EuroQol- 5 Dimensions of Health Visual Analogue Scale (EQ-5D VAS) records the participant's self-rated health on a vertical visual analogue scale, where the endpoints are scored from 0 to 100 i.e., 'The worst health you can imagine' (score of 0) to 'The best health you can imagine' (score of 100). Higher scores indicate better health outcomes.	At baseline and 1, 29, 57, 85, 180, 270, 365, 545, and 730 days post JCAR017 dose
Secondary	Number of Participants With Adverse Events (AEs)	An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant 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 participant's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) is also considered an AE. All participants were monitored for AEs during the study. Assessments included monitoring of any or all of the following parameters: the participant's clinical symptoms, laboratory, pathological, radiological or surgical findings, physical examination findings, or findings from other tests and/or procedures.	Up to 3 months after the dose of JCAR017 or after the last dose of the combination agent, whichever occurred last (an average of 6.5 months up until a max of 9.5 months)
Secondary	Number of Participants With Severe Adverse Events (SAEs)	An SAE is any AE occurring at any dose that: Results in death; Is life-threatening (i.e., in the opinion of the Investigator, the participant is at immediate risk of death from the AE); Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay); Results in persistent or significant disability/incapacity (a substantial disruption of the participant's ability to conduct normal life functions); Is a congenital anomaly/birth defect; Constitutes an important medical event.	Up to 3 months after the dose of JCAR017 or after the last dose of the combination agent, whichever occurred last (an average of 6.5 months up until a max of 9.5 months)
Secondary	Change From Baseline in White Blood Cell and Platelet Numbers	White blood cell, and platelet counts. Baseline is defined as the last measurement on or prior to any study treatment.	85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
Secondary	Change From Baseline in Percent of White Blood Cells	Change from baseline in percent of white blood cells was measured using differential blood tests. A differential blood test is a blood test that measures the percentage and number of each type of white blood cell (WBC) - neutrophils, lymphocytes, monocytes, eosinophils and basophils - as well as abnormal cell types if they are present. These results are reported as percentages and absolute values, and compared against reference ranges to determine whether the values are normal, low, or high. Baseline is defined as the last measurement on or prior to any study treatment.	85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
Secondary	Change From Baseline Erythrocyte Numbers	Change from baseline in erythrocyte (also known as red blood cell) numbers was measured using a test called a red blood cell count. Baseline is defined as the last measurement on or prior to any study treatment.	85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
Secondary	Change From Baseline Hematocrit Ratio	The change in the proportion of red blood cells in the blood was measured using a hematocrit test. A hematocrit test measures the volume of packed red blood cells relative to whole blood. This is represented as a ratio. Baseline is defined as the last measurement on or prior to any study treatment.	85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
Secondary	Change From Baseline in Hemoglobin Levels	The change from baseline in hemoglobin levels was measured using a hemoglobin test. A hemoglobin test measures the levels of hemoglobin in the blood. Hemoglobin is a protein in red blood cells that carries oxygen from the lungs to the rest of the body. Baseline is defined as the last measurement on or prior to any study treatment.	85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
Secondary	Change From Baseline in Specific Liver Serum Enzyme Levels	Change from baseline in alanine aminotransferase (ALT) alkaline phosphatase (ALP), and aspartate aminotransferase (AST). Baseline is defined as the last measurement on or prior to any study treatment.	85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
Secondary	Change From Baseline in Specific Serum Protein Levels	Change from baseline in serum albumin and protein levels. Serum protein level tests are blood tests that measure the number of proteins in the blood. Baseline is defined as the last measurement on or prior to any study treatment.	85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
Secondary	Change From Baseline in Serum Beta-2-Microglobulin Levels	Change from baseline in serum Beta-2-Microglobulin levels was measured using a beta-2 microglobulin (B2M) tumor marker test. Baseline is defined as the last measurement on or prior to any study treatment.	85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
Secondary	Change From Baseline in Serum Bicarbonate Levels	Change from baseline in serum bicarbonate levels was measured using a serum bicarbonate test. Baseline is defined as the last measurement on or prior to any study treatment.	85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
Secondary	Change From Baseline in Coagulation Times	Change from baseline in activated partial thromboplastin and prothrombin times. Activated partial thromboplastin time and prothrombin time are blood tests that measure how long it takes for blood to form a clot. Baseline is defined as the last measurement on or prior to any study treatment.	57 days after the dose of JCAR017
Secondary	Change From Baseline in D-Dimer Levels	D-dimer is a substance that is produced in the body when blood clots are broken down. The D-dimer laboratory test measures the level of D-dimer in the blood and is often used to help diagnose or rule out conditions related to blood clotting, such as deep vein thrombosis (DVT) or pulmonary embolism (PE). Elevated levels of D-dimer may indicate the presence of a blood clot, but other factors can also cause an increase in D-dimer levels. Therefore, the D-dimer test is typically used in combination with other diagnostic tests to help make an accurate diagnosis. Baseline is defined as the last measurement on or prior to any study treatment.	57 days after the dose of JCAR017
Secondary	Change From Baseline in Fibrinogen Levels	Fibrinogen is a protein that plays a role in a number of processes in the body, including blood clot formation, wound healing, inflammation, and blood vessel growth. Baseline is defined as the last measurement on or prior to any study treatment.	57 days after the dose of JCAR017
Secondary	Change From Baseline in Prothrombin International Normalized Ratio	The Prothrombin International Normalized Ratio (INR) is used to determine the clotting tendency of blood. The INR is derived from prothrombin time (PT) which is calculated as a ratio of the patient's PT to a control PT. Baseline is defined as the last measurement on or prior to any study treatment.	57 days after the dose of JCAR017
Secondary	Progression-Free Survival (PFS)	PFS is defined as time from JCAR017 infusion to disease progression or death from any cause.; Progressive disease (PD) was measured using CT and PET as an increase in size index and non-index lesions, spleen size, and the presence of new lesions or diseased bone marrow.; Summarized using Kaplan-Meier estimates.	From JCAR017 infusion to disease progression or death from any cause (up to approximately 62 months)
Secondary	Overall Survival (OS)	Time from JCAR017 infusion to death. Data from surviving participants was censored at the last time that the participant was known to be alive.; Summarized using Kaplan-Meier estimates.	From start of JCAR017 to time of death from any cause, or data cut-off date, whichever occurred first (up to approximately 62 months)
Secondary	Overall Response Rate (ORR)	The ORR is the percent of participants achieving an objective response of partial response (PR) or better according to the Lugano Criteria for Response Assessment (Cheson, 2014), prior to start of another non-study anticancer therapy.; Complete response (CR) assessed by CT-scan: Index lesions: Nodal Disease: = 1.5 cm in largest transverse diameter, Extranodal Disease: Absent; Non-index lesions: Absent,; Spleen: <13 cm; New lesions: None; Bone marrow: Normal; Partial response (PR) assessed by CT-scan: Index lesions: >=50% decrease from baseline in shortest diameter; Non-index lesions: No increase,; Spleen: >50% decrease from baseline in enlarged portion; New lesions: None; Bone marrow: N/A Overall Response (OR) = CR + PR	At 1, 3, 6, 9, 12, 18 and 24 months post-JCAR017 infusion
Secondary	Duration of Response (DOR)	DOR is defined as the time from first response to disease progression or death from any cause.; Summarized using Kaplan-Meier estimates.	From JCAR017 infusion to disease progression or death from any cause (up to approximately 62 months)
Secondary	Event-Free Survival (EFS)	EFS is defined as time from JCAR017 infusion to disease progression, starting a new antilymphoma therapy, or death from any cause, whichever occurred first.	From JCAR017 infusion to disease progression or death from any cause (up to approximately 62 months)
Secondary	Maximum Concentration (Cmax) of JCAR017 by qPCR	Cmax is the maximum or peak concentration of drug reached in the plasma following a dose of the drug.; qPCR was used to determine Cmax by detecting the JCAR017 transgene.	Up to 24 months post- JCAR017 infusion
Secondary	Time to Maximum Concentration (Tmax) of JCAR017 by qPCR	Time to maximum concentration (Tmax) is the time it takes for a drug to reach the maximum concentration (Cmax) after administration.; qPCR was used to determine Tmax by detecting the JCAR017 transgene.	Up to 24 months post- JCAR017 infusion
Secondary	Total Exposure to JCAR017 as Measured by the Area Under the Curve (AUC) by qPCR	Area Under the Curve" (AUC) represents the total exposure of participants to study drug. qPCR was used to determine AUC by detecting the JCAR017 transgene.	Up to 24 months post- JCAR017 infusion

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