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Recurrent ALK Positive Large B-Cell LymphomaPhase 2NCT05507541

TTI-622 in Combination With Pembrolizumab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma

A Phase 2 study testing Biospecimen Collection, Computed Tomography and Ontorpacept in people with Recurrent ALK Positive Large B-Cell Lymphoma and Recurrent B-Cell Non-Hodgkin Lymphoma, run by Mayo Clinic at 2 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Biospecimen Collection, Computed Tomography and Ontorpacept
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
2 sitesUnited States
Study dates
19 Apr 2023to 30 Jul 2027
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
Show all 48Show fewer
  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • University of Iowa

    Iowa City, Iowa, 52242

  • Mayo Clinic

    Rochester, Minnesota, 55905

Other trials in United States

About this study

Official title: Phase 2 Study With Safety run-in of PD-1 Inhibitor and IgG4 SIRPα-Fc Fusion Protein (TTI-622) in Relapsed Diffuse Large B-Cell Lymphoma (DLBCL)

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\&#39;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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. 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.

Being tested
Biospecimen Collection, Computed Tomography, Ontorpacept, Pembrolizumab, Positron Emission Tomography
Medical subject headings
Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection, Blood Sample Collection

    Undergo blood sample collection

  • Computed TomographyProcedure or surgery

    Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography

    Undergo PET/CT or CT scan

  • OntorpaceptDrug

    Also called SIRPa-Fc Fusion Protein TTI-621, SIRPaFc, TTI 621, TTI-621

    Given IV

  • PembrolizumabBiological

    Also called Keytruda, Lambrolizumab, MK-3475, SCH 900475

    Given IV

  • Positron Emission TomographyProcedure or surgery

    Also called Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron Emission Tomography Scan

    Undergo PET/CT scans

  • MaplirpaceptDrug

    Also called SIRPa-IgG4 Fc, SIRPa-IgG4 Fc TTI-622, TTI 622, TTI-622

    Given IV

  • BiopsyProcedure or surgery

    Also called BIOPSY_TYPE, Bx

    Undergo tumor biopsy

Study groups in NCT05507541
Study groupRoleWhat they receive
Arm A (pembrolizumab, TTI-621) -- CLOSED TO ACCRUAL 8/16/2024ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 of each cycle and 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 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.
Receives: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Ontorpacept; Biological: Pembrolizumab; Procedure: Positron Emission Tomography; Procedure: Biopsy
Arm B (pembrolizumab, TTI-622)ExperimentalPatients 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 days 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.
Receives: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Pembrolizumab; Procedure: Positron Emission Tomography; Drug: Maplirpacept; Procedure: Biopsy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Recommended phase 2 dose of maplirpacept (TTI-622) when given in combination with pembrolizumab (Safety run-in)

    Defined as the highest dose for which at most 1 out of 6 subjects experience significant toxicity during the 6-week safety assessment period. Toxicity will be measured per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. Significant toxicity is defined as an adverse event occurring during the first cycle of treatment that is possibly, probably, or definitely related to study treatment.

    Measured: Up to 6 weeks

  2. Overall response (Phase 2)

    A success is defined as an objective status of partial metabolic response (PMR) or complete metabolic response (CMR) by positron emission tomography-computed tomography (PET-CT) based criteria at any time. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Note: For patients where PET/CT scan was not available due to insurance coverage and who received a CT scan only, they will still be considered evaluable for the primary endpoint and will be included in the denominator for estimating overall response rate. In these patients, the CT-based responses will be reported descriptively.

    Measured: Up to 2 years

Secondary outcomes (4)

  1. Duration of response (DOR) (Phase 2)

    Defined for all evaluable patients who have achieved an objective response as the date at which the patient's objective status is first noted to be either a CMR or PMR to first documentation of disease progression. DOR will be descriptively summarized.

    Measured: Up to 2 years

  2. Incidence of adverse events (AEs) (Phase 2)

    All eligible patients that have initiated treatment will be considered evaluable for assessing AE rate(s). The maximum grade for each type of AE will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the AE(s) to the study treatment will be taken into consideration.

    Measured: Up to 2 years

  3. Overall survival (OS) (Phase 2)

    OS is defined as the time from registration to death due to any cause.

    Measured: up to 2 years

  4. Progression-free survival (PFS) (Phase 2)

    PFS is defined as the time from registration to the first documentation of disease progression [progressive metabolic disease (PMD) or progressive disease (PD)] or death due to any cause in the absence of documented progression.

    Measured: Up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Aug 2022
  2. Study start19 Apr 2023
  3. Primary completion30 Jul 2027 (estimated)
  4. Study completion30 Jul 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05507541
Sponsor's protocol ID
MC200802
Other IDs
21-003869
Status last verified
Apr 2026
First submitted
17 Aug 2022
Last updated
22 Apr 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Duell J, Westin J. The future of immunotherapy for diffuse large B-cell lymphoma. Int J Cancer. 2025 Jan 15;156(2):251-261. doi: 10.1002/ijc.35156. Epub 2024 Sep 25.

    PubMed 39319495

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