Trial Title:
TTI-622 in Combination with Pembrolizumab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma
NCT ID:
NCT05507541
Condition:
Recurrent ALK Positive Large B-Cell Lymphoma
Recurrent B-Cell Non-Hodgkin Lymphoma
Recurrent Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation
Recurrent Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
Recurrent EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
Recurrent Grade 3b Follicular Lymphoma
Recurrent High Grade B-Cell Lymphoma
Recurrent High Grade B-Cell Lymphoma with MYC and BCL2 or BCL6 Rearrangements
Recurrent High Grade B-Cell Lymphoma with MYC, BCL2, and BCL6 Rearrangements
Recurrent High Grade B-Cell Lymphoma, Not Otherwise Specified
Recurrent Intravascular Large B-Cell Lymphoma
Recurrent Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma
Recurrent T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
Refractory ALK Positive Large B-Cell Lymphoma
Refractory Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation
Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
Refractory EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
Refractory Grade 3b Follicular Lymphoma
Refractory High Grade B-Cell Lymphoma
Refractory High Grade B-Cell Lymphoma with MYC and BCL2 or BCL6 Rearrangements
Refractory High Grade B-Cell Lymphoma with MYC, BCL2, and BCL6 Rearrangements
Refractory High Grade B-Cell Lymphoma, Not Otherwise Specified
Refractory Intravascular Large B-Cell Lymphoma
Refractory Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
Refractory Primary Mediastinal Large B-Cell Lymphoma
Refractory T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
Recurrent Gray Zone Lymphoma
Conditions: Official terms:
Lymphoma
Lymphoma, Follicular
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Recurrence
Inflammation
Pembrolizumab
Immunoglobulin G
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Arm A (pembrolizumab, TTI-621) -- CLOSED TO ACCRUAL 8/16/2024
Arm group label:
Arm B (pembrolizumab, TTI-622)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Other name:
Blood Sample Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo PET/CT or CT scan
Arm group label:
Arm A (pembrolizumab, TTI-621) -- CLOSED TO ACCRUAL 8/16/2024
Arm group label:
Arm B (pembrolizumab, TTI-622)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized Tomography
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Other name:
Computerized axial tomography (procedure)
Intervention type:
Drug
Intervention name:
Ontorpacept
Description:
Given IV
Arm group label:
Arm A (pembrolizumab, TTI-621) -- CLOSED TO ACCRUAL 8/16/2024
Other name:
SIRPa-Fc Fusion Protein TTI-621
Other name:
SIRPaFc
Other name:
TTI 621
Other name:
TTI-621
Intervention type:
Biological
Intervention name:
Pembrolizumab
Description:
Given IV
Arm group label:
Arm A (pembrolizumab, TTI-621) -- CLOSED TO ACCRUAL 8/16/2024
Arm group label:
Arm B (pembrolizumab, TTI-622)
Other name:
Keytruda
Other name:
Lambrolizumab
Other name:
MK-3475
Other name:
SCH 900475
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET/CT scans
Arm group label:
Arm A (pembrolizumab, TTI-621) -- CLOSED TO ACCRUAL 8/16/2024
Arm group label:
Arm B (pembrolizumab, TTI-622)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
Positron emission tomography (procedure)
Intervention type:
Drug
Intervention name:
Maplirpacept
Description:
Given IV
Arm group label:
Arm B (pembrolizumab, TTI-622)
Other name:
SIRPa-IgG4 Fc
Other name:
SIRPa-IgG4 Fc TTI-622
Other name:
TTI 622
Other name:
TTI-622
Other name:
TTI622
Other name:
SIRPa-IgG4-Fc Fusion Protein TTI-622
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo tumor biopsy
Arm group label:
Arm A (pembrolizumab, TTI-621) -- CLOSED TO ACCRUAL 8/16/2024
Arm group label:
Arm B (pembrolizumab, TTI-622)
Other name:
BIOPSY_TYPE
Other name:
Bx
Summary:
This phase II trial tests the safety, side effects, and best dose of TTI-621 (closed to
enrollment) or TTI-622 in combination with pembrolizumab in treating patients with
diffuse large B-cell lymphoma that has come back after a period of improvement (relapsed)
or that does not respond to treatment (refractory). TTI-621 and TTI-622 are called fusion
proteins. A fusion protein includes two specialized proteins that are joined together. In
TTI-621 and TTI-622, one of the proteins binds with other proteins found on the surface
of certain cells that are part of the immune system. The other protein targets and blocks
a protein called CD47. CD47 is present on cancer cells and is used by those cells to hide
from the body's immune system. By blocking CD47, TTI-621 and TTI-622 may help the immune
system find and destroy cancer cells. Pembrolizumab is a monoclonal antibody directed
against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1)
that works by helping the body's immune system attack the cancer and may interfere
with the ability of cancer cells to grow and spread. Giving TTI-621 (closed to
enrollment) or TTI-622 in combination with pembrolizumab may kill more cancer cells in
patients with relapsed or refractory diffuse large B-cell lymphoma.
Detailed description:
PRIMARY OBJECTIVES:
I. To determine the toxicities of maplirpacept (TTI-622) combined with pembrolizumab and
to identify the recommended phase 2 dose (RP2D) of TTI-622, combined with pembrolizumab.
(Safety run-in) II. To estimate preliminary efficacy of pembrolizumab in combination with
TTI-622 as measured by overall response rate (ORR). (Phase 2).
SECONDARY OBJECTIVE:
I. To estimate efficacy of pembrolizumab in combination with TTI-622 as measured by
duration of response (DOR), progression free survival (PFS), and overall survival (OS).
CORRELATIVE OBJECTIVE:
I. Correlation of biomarkers measured in serial peripheral blood samples and tumor
tissues with clinical responses, which may include but are not limited to: SIRPalpha
expression, monocyte/macrophage markers in tumor micro-environment, tumor infiltrating
lymphocytes (TILs), PD-1/PDL-1 expression.
OUTLINE: Patients are assigned to 1 of 2 arms. Patients enrolling after 8/16/2024 are
assigned to Arm B.
ARM A (CLOSED TO ACCRUAL AS OF 8/16/2024): Patients receive pembrolizumab intravenously
(IV) over 30 minutes on day 1 of each cycle and ontorpacept (TTI-621) IV over 60-120
minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 12 cycles in
the absence of disease progression or unacceptable toxicity. Patients also undergo
positron emission tomography/computed tomography (PET/CT) scans or CT scans of the chest,
abdomen, and pelvis prior to cycle 3 and every 4 cycles thereafter. If no disease
progression after cycle 12, patients then receive pembrolizumab IV over 30 minutes on day
1 of each cycle and TTI-621 IV over 60 minutes on day 1 of each cycle. Treatment repeats
every 21 days for up to 23 cycles in the absence of disease progression or unacceptable
toxicity. Patients also undergo PET/CT and/or CT and blood sample collection throughout
the study. Patients may undergo biopsy on study.
ARM B: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle and
TTI-622 IV over 60-90 minutes on day 1 of each cycle. Treatment repeats every 21 days for
up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients
also undergo PET/CT scans or CT scans of the chest, abdomen, and pelvis prior to cycle 3
and every 4 cycles thereafter. If no disease progression after cycle 12, patients then
receive pembrolizumab IV over 30 minutes on day 1 of each cycle and TTI-622 IV over 60-90
minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 23 cycles in
the absence of disease progression or unacceptable toxicity. Patients also undergo PET/CT
and/or CT and blood sample collection throughout the study. Patients may undergo biopsy
on study.
After completion of the study treatment, patients are followed every 6 months for up to 2
years from registration.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age >= 18 years
- Documented CD20+ mature B-cell neoplasm according to World Health Organization (WHO)
classification (Swerdlow et al., 2016) as one of the following:
- Diffuse large B-cell lymphoma not otherwise specified (NOS) including
- Transformed lymphoma
- Richter's transformation
- Germinal center B-cell type
- Activated B-cell type
- High-grade B-cell lymphoma (HGBCL), NOS
- Primary mediastinal (thymic) large B-cell lymphoma
- Patients with "double-hit" or "triple-hit" diffuse large B-cell lymphoma
(DLBCL) (technically as HGBCL, with MYC and BCL2 and/or BCL6 rearrangements)
- Follicular lymphoma 3B
- T-cell/histiocyte-rich large B cell lymphoma
- Large B-cell lymphoma with IRF4 rearrangement
- Primary cutaneous DLBCL, leg type
- Epstein-Barr virus (EBV) positive DLBCL, NOS
- DLBCL associated with chronic inflammation
- Intravascular large B-cell lymphoma
- ALK positive large B-cell lymphoma
- Relapsed, progressive and/or refractory disease (Cheson et al., 2007) following
treatment with an anti-CD20 monoclonal antibody (e.g., rituximab) in combination
with chemotherapy
- Measurable disease as defined below:
- Fluorodeoxyglucose (FDG)-avid lymphomas: Measurable disease with computerized
tomography (CT) (or magnetic resonance imaging [MRI]) scan with involvement of
2 or more clearly demarcated lesions/nodes with a long axis > 1.5 cm and short
axis > 1.0 cm (or 1 clearly demarcated lesion/node with a long axis > 2.0 cm
and short axis >= 1.0 cm) AND FDG positron emission tomography (PET) scan that
demonstrates positive lesion(s) compatible with CT (or MRI) defined anatomical
tumor sites
- FDG-nonavid lymphomas: Measurable disease with CT (or MRI) scan with
involvement of 2 or more clearly demarcated lesions/nodes with a long axis >
1.5 cm and short axis > 1.0 cm or 1 clearly demarcated lesion/node with a long
axis > 2.0 cm and short axis >= 1.0 cm.
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
- >= 4 weeks from last dose of anti-CD20 targeting therapy
- >= 12 weeks post chimeric antigen receptor (CAR) T-cell therapy
- Resolution of all adverse events due to prior therapy to =< Grade 1 or baseline
NOTE: Patients with =< Grade 2 neuropathy may be eligible. Patients with
endocrine-related adverse events (AEs) Grade =< 2 requiring treatment or hormone
replacement may be eligible
- If receiving glucocorticoid treatment at screening, treatment must be tapered down
and administered with a maximum of 10 mg daily in the last 14 days prior to
registration
- Absolute neutrophil count (ANC) >= 500/mm^3; growth factor support allowed in case
of bone marrow involvement (obtained =< 7 days prior to registration)
- Absolute lymphocyte count >= 200/mm^3 (obtained =< 7 days prior to registration)
- Platelet count >= 75,000/mm^3 (obtained =< 7 days prior to registration)
- Hemoglobin >= 8.0 g/dL (obtained =< 7 days prior to registration)
- International normalized ratio (INR) or activated partial thromboplastin time (aPTT)
=< 1.5 × upper limit of normal (ULN) unless participant is receiving anticoagulant
therapy as long as prothrombin time (PT) or aPTT is within therapeutic range of
intended use of anticoagulants (obtained =< 7 days prior to registration)
- Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's
disease (direct bilirubin [bili] =< ULN) (obtained =< 7 days prior to registration)
- Aspartate transaminase [AST/serum glutamic oxaloacetic transaminase (SGOT)] and
alanine transaminase [ALT/serum glutamic pyruvic transaminase (SGPT)] =< 2.5 x ULN
(obtained =< 7 days prior to registration)
- Calculated creatinine clearance >=30 mL/min using the Cockcroft-Gault formula
(obtained =< 7 days prior to registration)
- Provide informed written consent
- Negative pregnancy test done =< 3 days prior to registration, for persons of
childbearing potential only
- Female of childbearing must agree to use a highly effective method of contraception
during the treatment and for 120 days after the last dose of study treatment
- Male participants with female partners of childbearing potential must agree to
refrain from donating sperm and one of the conception methods during the treatment
and for 120 days after last dose study treatment
- Willing to return to the enrolling institution for follow-up (during the active
monitoring phase of the study)
- Willing to provide mandatory tissue and blood samples for correlative research
purposes
Exclusion Criteria:
- Primary central nervous system (CNS) lymphoma or known CNS involvement by lymphoma
at screening as confirmed by magnetic resonance imaging (MRI)/computed tomography
(CT) scan (brain) and, if clinically indicated, by lumbar puncture
- Known past or current malignancy other than inclusion diagnosis, except for:
- Cervical carcinoma of Stage 1B or less
- Non-invasive basal cell or squamous cell skin carcinoma
- Non-invasive, superficial bladder cancer
- Prostate cancer with a current prostate specific antigen (PSA) level < 0.1
ng/mL
- Any curable cancer with a complete response (CR) of > 2 years duration
- Received < 2 prior systemic anti-cancer therapy including investigational agents =<
4 weeks or =< 5 half-lives, whichever is shorter, prior to registration
- Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX-40, CD137) =< 4 weeks prior to registration
- Known clinically significant cardiac disease, including:
- Onset of unstable angina pectoris within 6 months of signing informed consent
form (ICF)
- Acute myocardial infarction within 6 months of signing ICF
- Congestive heart failure (grade III or IV as classified by the New York Heart
Association and/or known decrease ejection fraction of < 45%)
- Chronic ongoing infectious diseases (except hepatitis B or hepatitis C) requiring
treatment (excluding prophylactic treatment) at the time of enrollment or =< the
previous 2 weeks
- Confirmed history or current autoimmune disease or other diseases resulting in
permanent immunosuppression or requiring permanent immunosuppressive therapy or
primary immunodeficiency disorder. Low-dose steroids (=< 10 mg daily of prednisone
equivalent) is allowed
- Seizure disorder requiring therapy (such as steroids or anti-epileptics)
- Autologous hematopoietic stem cell transplant (HSCT) =< 100 days prior or any prior
allogeneic HSCT or solid organ transplantation
- Known human immunodeficiency virus (HIV) infection
- Exposed to live or live attenuated vaccine =< 4 weeks prior to registration
- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:
- Pregnant persons
- Nursing persons
- Persons of childbearing potential who are unwilling to employ adequate
contraception
- Patient has any condition for which, in the opinion of the investigator,
participation would not be in the best interest of the patient (e.g., compromise the
well-being) or that could prevent, limit, or confound the protocol-specified
assessments
- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens
- Uncontrolled intercurrent illness including, but not limited to:
- ongoing or active infection
- uncontrolled infection requiring ongoing antibiotics
- symptomatic congestive heart failure
- unstable angina pectoris
- cardiac arrhythmia
- or psychiatric illness/social situations that would limit compliance with
study requirements
- known substance abuse disorder
- Known hypersensitivity to pembrolizumab
- Major surgery other than diagnostic surgery =< 4 weeks prior to registration
- Prior radiation therapy =< 2 weeks prior to registration or who has not recovered
from all radiation-related toxicities, not require corticosteroids, and not have had
radiation pneumonitis. Note: A 1-week washout is permitted for palliative radiation
(=< 2 weeks of radiotherapy) to non-CNS disease
- Active autoimmune disease such as Crohn's disease, rheumatoid arthritis, Sjogren's
disease, systemic lupus erythematosus, or similar conditions requiring systemic
treatment =< the past 3 months or a documented history of clinically severe
autoimmune disease/syndrome difficult to control in the past.
EXCEPTIONS:
- Vitiligo or resolved childhood asthma/atopy
- Intermittent use of bronchodilators or local steroid injections
- Hypothyroidism stable on hormone replacement,
- Diabetes stable with current management
- History of positive Coombs test but no evidence of hemolysis
- Psoriasis not requiring systemic treatment
- Conditions not expected to recur in the absence of an external trigger
- Has a known history of hepatitis B (defined as hepatitis B surface antigen
[HBsAg] reactive) or known active hepatitis C virus (HCV) (defined as HCV
ribonucleic acid [RNA] is detected) infection
- Prior anti CD47 therapy
- Active use of anticoagulant like warfarin. Use of low molecular weight heparin
and factor Xa inhibitors will be permitted on case by case basis. There will be
no restriction for daily aspirin < 81mg daily
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of Iowa
Address:
City:
Iowa City
Zip:
52242
Country:
United States
Status:
Recruiting
Contact:
Last name:
Jussara Hagen
Phone:
319-356-4200
Email:
jussara-hagen@uiowa.edu
Contact backup:
Last name:
Eric Mou, MD
Facility:
Name:
Mayo Clinic
Address:
City:
Rochester
Zip:
55905
Country:
United States
Status:
Recruiting
Contact:
Last name:
Clinical Trials Referral Office
Phone:
855-776-0015
Email:
mayocliniccancerstudies@mayo.edu
Contact backup:
Last name:
Stephen M. Ansell, MD, PhD
Start date:
April 19, 2023
Completion date:
November 1, 2027
Lead sponsor:
Agency:
Mayo Clinic
Agency class:
Other
Source:
Mayo Clinic
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05507541
https://www.mayo.edu/research/clinical-trials
