Description:
The purpose of this study is to find the maximum dose of huCART19-IL18 cells that is safe for
use in humans with Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Title
- Brief Title: huCART19-IL18 in NHL/CLL Patients
- Official Title: Phase I Trial of huCART19-IL18 Cells in Patients With Relapsed or Refractory CD19+ Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)
Clinical Trial IDs
- ORG STUDY ID:
UPCC15420
- NCT ID:
NCT04684563
Conditions
- Chronic Lymphocytic Leukemia
- Non-hodgkin Lymphoma
Interventions
Drug | Synonyms | Arms |
---|
huCART19-IL18 | | Dose Level -1 (DL-1) |
Purpose
The purpose of this study is to find the maximum dose of huCART19-IL18 cells that is safe for
use in humans with Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Detailed Description
This is a Phase I dose finding study to determine the maximum tolerated dose (MTD) and assess
the safety, tolerability, manufacturing feasibility, pharmacokinetics, and preliminary
efficacy of huCART19-IL18 cells in patients with Non-Hodgkin Lymphoma (NHL) and Chronic
Lymphocytic Leukemia (CLL). This trial will evaluate up to 7 dose levels using the Bayesian
Optimal Interval (BOIN) design with accelerated titration to determine the maximum tolerated
dose (MTD) of huCART19-IL18 cells. Subjects will be assigned to a dose level prior to study
treatment based on available safety experience at the current and prior dose levels.
huCART19-IL18 cells will be administered to all subjects as a single intravenous (IV)
infusion or slow IV push, depending on the assigned dose level. For consistency, the
huCART19-IL18 infusions will be identified as IV infusions throughout the protocol.
.
Trial Arms
Name | Type | Description | Interventions |
---|
Dose Level 1a (DL1a) | Experimental | 3x10^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push | |
Dose Level -1 (DL-1) | Experimental | 7x10^5 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 1a. | |
Dose Level 1b (DL1b) | Experimental | 3x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | |
Dose Level 2 (DL2) | Experimental | 7x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | |
Dose Level 3 (DL3) | Experimental | 3x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | |
Dose Level 4 (DL4) | Experimental | 7x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | |
Dose Level 5 (DL5) | Experimental | 3x10^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | |
Eligibility Criteria
Inclusion Criteria:
1. Signed informed consent form
2. Documentation of CD19 expression on malignant cells
1. CLL: At time of most recent relapse
2. NHL: Within 6 months of physician-investigator confirmation of eligibility as
long as there has been no intervening CD19 directed therapy since expression
confirmed. Results outside of this window may be used, if there is no accessible
tumor site and the subject did not receive intervening CD19 directed therapy
since CD19 expression was confirmed.
3. Patients with relapsed disease after prior allogeneic SCT must meet the following
criteria:
1. Have no active GVHD and require no immunosuppression
2. Are more than 6 months from transplant at the time of physician-investigator
confirmation of eligibility
4. Adequate organ function defined as:
a. Creatinine ≤ 1.6 mg/dl b. ALT/AST ≤ 3x upper limit of normal range c. Direct
bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert's syndrome (≤3.0 mg/dl) d. Must
have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse
oxygen > 92% on room air e. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by
ECHO/MUGA
5. Evidence of active disease. This could include circulating disease in the blood,
disease in the bone marrow by standard morphology, or in NHL patients, measurable
disease per Lugano criteria.
6. Male or female age ≥ 18 years.
7. ECOG Performance Status that is either 0 or 1.
8. Subjects of reproductive potential must agree to use acceptable birth control methods,
as described in protocol
9. Disease-specific criteria:
a. Chronic Lymphocytic Leukemia (CLL): i. Patients with relapsed/refractory disease
after at least 2 prior lines of appropriate therapy; and ii. Patients must have
previously received, or be intolerant to an approved BTK inhibitor and venetoclax,
unless a BTK inhibitor or venetoclax is contraindicated.
b. Non-Hodgkin Lymphoma (NHL): i. Patients with any of the following diagnoses:
Diffuse Large B-cell Lymphoma not otherwise specified (DLBCL NOS), germinal center or
activated B-cell types; Primary Cutaneous DLBCL; Primary Mediastinal (thymic) Large
B-cell Lymphoma; ALK+ Anaplastic Large B-cell Lymphoma; High-Grade B-cell Lymphoma
with MYC and BCL2 and/or BCL6 rearrangements (i.e. "Double or Triple Hit"); High-grade
B-cell Lymphoma, NOS; T-cell Rich B-cell Lymphoma; Transformed Follicular Lymphoma; or
any aggressive B-cell lymphoma arising from indolent lymphoma.
1. Patients must have either relapsed after, or be ineligible for, prior CAR T cell
therapy, and meet one of the following criteria:
1. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy and
are ineligible for autologous stem cell transplant or commercial CAR T cell therapy.
2. Relapsed/refractory disease after autologous SCT.
3. Relapsed/refractory disease after allogeneic SCT. ii. Follicular lymphoma 1. Patients
who have received at least 2 prior lines of appropriate therapy (not including single
agent monoclonal antibody therapy) and progressed within 2 years after second or
higher line of therapy.
iii. Mantle cell lymphoma
1. Patients must have either failed or be ineligible for standard of care Tecartus™
(brexucabtagene autoleucel) or other investigational CAR T cell product; and
2. Patients must also meet one of the following criteria:
1. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy,
including a BTK inhibitor. Single-agent monoclonal antibody therapy does not
count towards prior lines of therapy.
2. Relapsed/refractory disease after prior autologous SCT.
3. Relapsed/refractory disease after prior allogeneic SCT. iv. Large cell
transformation of CLL (Richter's Transformation)
1. Patients must be primary refractory or received at least 1 prior line of treatment.
Exclusion Criteria:
1. Active hepatitis B, active hepatitis C, or other active, uncontrolled infection.
2. Class III/IV cardiovascular disability according to the New York Heart Association
Classification
3. Clinically apparent arrhythmia or arrhythmias that are not stable on medical
management within two weeks of physician-investigator confirmation of eligibility.
4. Active acute or chronic GVHD requiring systemic therapy.
5. Dependence on systemic steroids or immunosuppressant medications. For additional
details regarding use of steroid and immunosuppressant medications
6. Receipt of immune checkpoint inhibitors within 4 months prior to
physician-investigator confirmation of eligibility.
7. Receipt of prior huCART19 therapy.
8. Active CNS disease. Note: Patients with a history of CNS involvement that was
successfully treated are eligible. A CNS evaluation is only required for eligibility
if a subject is experiencing signs/symptoms of CNS involvement.
9. Pregnant or nursing (lactating) women.
10. Patients with a known history or prior diagnosis of optic neuritis or other
immunologic or inflammatory disease affecting the central nervous system, and
unrelated to their cancer or previous cancer treatment.
11. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to
≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will
be excluded.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0. |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Secondary Outcome Measures
Measure: | Percentage of manufacturing products that meet release criteria. |
Time Frame: | 3 months |
Safety Issue: | |
Description: | |
Measure: | Number of subjects who have a response |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Measure: | Best Overall Response (BOR) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Measure: | Duration of Response (DOR) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Measure: | Overall Survival (OS) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Measure: | Progression free survival (PFS) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | University of Pennsylvania |
Trial Keywords
Last Updated
May 11, 2021