TTI-621/TTI-622 + Pembrolizumab for Lymphoma

Not currently recruiting at 2 trial locations

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Anticoagulants, Anti-PD-1 agents

Disqualifiers: CNS lymphoma, Cardiac disease, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 9

Duration: 36 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a new combination of treatments might help individuals with diffuse large B-cell lymphoma that has returned or hasn't responded to previous treatments. It uses fusion proteins, TTI-621 and TTI-622, along with pembrolizumab, a medication that helps the immune system attack cancer cells. The aim is to determine the best dose and understand the safety and side effects of this combination. This trial might suit someone whose lymphoma has returned or is not responding to treatments after using an anti-CD20 monoclonal antibody, such as rituximab, with chemotherapy. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on glucocorticoid treatment, it must be reduced to a maximum of 10 mg daily in the last 14 days before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatments studied in this trial, TTI-621 and TTI-622, have promising safety records from earlier studies. Patients with certain types of cancer, such as mycosis fungoides, generally tolerated TTI-621 well. Most side effects were manageable, allowing patients to continue treatment.

Similarly, TTI-622 underwent safety testing in people with relapsed or hard-to-treat lymphomas. It was also generally well tolerated, with only mild to moderate side effects reported.

Pembrolizumab, already approved for other cancers, has extensive safety data available. It is generally well tolerated, though it can cause side effects like tiredness or skin reactions.

Overall, the available data suggest these treatments have been safe for most patients in past studies. However, individual reactions can vary, so discussing any concerns with the trial team is always important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments TTI-621 and TTI-622 combined with pembrolizumab because they offer a novel approach to tackling lymphoma. Unlike most standard lymphoma treatments, which often rely on chemotherapy or other immune checkpoint inhibitors, TTI-621 and TTI-622 target the CD47-SIRPα axis, a mechanism that helps cancer cells evade the immune system. By blocking this pathway, these treatments aim to enhance the body's ability to detect and destroy cancer cells. The combination with pembrolizumab, a known immune checkpoint inhibitor, could potentially amplify the immune response, offering hope for more effective outcomes in patients with lymphoma.

What evidence suggests that this trial's treatments could be effective for relapsed or refractory diffuse large B-cell lymphoma?

Research has shown that blocking a protein called CD47 with treatments like TTI-621 and TTI-622 may help the immune system attack cancer cells. In studies, TTI-621 shrank tumors in 22% of patients with cancer that had returned or was not responding to other treatments. TTI-622 showed early positive results in similar patients and was generally safe, causing no serious side effects for most people. In this trial, participants will receive either TTI-621 or TTI-622 combined with Pembrolizumab, another treatment that helps the immune system fight various cancers, including lymphoma. Together, these treatments aim to enhance the body's ability to find and destroy cancer cells, offering new hope for those with hard-to-treat lymphoma. ^{4 6 7 8 9}

Who Is on the Research Team?

Stephen M. Ansell, M.D.

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

Adults with relapsed or refractory diffuse large B-cell lymphoma can join this trial. They must have had prior treatment with an anti-CD20 monoclonal antibody and chemotherapy, be in good physical condition, and not have other current cancers or severe diseases. Women of childbearing age need to use effective contraception.

Inclusion Criteria

Negative pregnancy test done =< 3 days prior to registration for persons of childbearing potential

Willing to provide tissue and blood samples for research purposes

Provide informed written consent

Exclusion Criteria

I am HIV positive.

I have or had cancer types other than the one I am seeking treatment for.

I have a long-term infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-in

Determine the toxicities and identify the recommended phase 2 dose of TTI-622 combined with pembrolizumab

6 weeks

1 visit every 21 days

Treatment

Patients receive pembrolizumab and TTI-622 intravenously every 21 days for up to 12 cycles, with PET/CT scans prior to cycle 3 and every 4 cycles thereafter

36 weeks

1 visit every 21 days

Extended Treatment

If no disease progression after 12 cycles, treatment continues with pembrolizumab and TTI-622 every 21 days for up to 23 cycles

69 weeks

1 visit every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 2 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• TTI-621
• TTI-622

Trial Overview The trial is testing the safety and optimal doses of TTI-621 or TTI-622 combined with pembrolizumab. These fusion proteins may help the immune system detect and destroy cancer cells by blocking a protein called CD47 that cancer cells use to avoid immune detection.

How Is the Trial Designed?

Group I: Arm B (pembrolizumab, TTI-622) Experimental Treatment 6 Interventions

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 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.

Group II: Arm A (pembrolizumab, TTI-621) -- CLOSED TO ACCRUAL 8/16/2024 Experimental Treatment 6 Interventions

Patients 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.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

A 70-year-old woman developed immune checkpoint inhibitor (ICI)-related myocarditis and new-onset myasthenia gravis (MG) after starting pembrolizumab for metastatic thymic cancer, highlighting potential serious side effects of this treatment.

Despite the adverse effects, the patient showed significant improvement in her metastatic disease after 6 weeks, indicating that pembrolizumab can be effective in reducing tumor burden even in the presence of severe immune-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checkpoint inhibitor-induced myocarditis and myasthenia gravis in a recurrent/metastatic thymic carcinoma patient: a case report. Szuchan, C., Elson, L., Alley, E., et al.[2022]

Pembrolizumab, an anti-PD-1 therapy, shows a high objective response rate of 84.5% in patients with refractory or recurrent NK/T-cell lymphoma, indicating its efficacy as a treatment option.

The treatment resulted in a complete response rate of 61.6% and demonstrated good disease-free survival ranging from 2 to 48 months, with low adverse events reported, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of PD-1 blockade in refractory/relapsed natural killer T-cell lymphomas: a systematic review and synthesis of case reports. Rivera-Francia, VM., Failoc-Rojas, VE., Villacorta-Carranza, R., et al.[2023]

In a study of 59 patients with relapsed/refractory extranodal natural killer/T-cell lymphoma treated with pembrolizumab, the overall response rate was 40.7%, with 28.8% achieving a complete response, indicating its potential efficacy as a salvage therapy.

While pembrolizumab showed modest effectiveness, it was associated with some grade 3 or 4 adverse events in 20.3% of patients, with neutropenia being the most common, suggesting that while it can be beneficial, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma in Korea. Lee, JY., Kwon, JH., Hur, JY., et al.[2023]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor used for treating non-small cell lung cancer, is generally well tolerated, but can lead to rare immune-mediated adverse effects such as pleuropericarditis, as seen in a case involving a 64-year-old female patient.

The patient was effectively treated with colchicine, furosemide, and methylprednisolone, leading to symptom improvement and a decision to discontinue pembrolizumab, after which she remained asymptomatic for six months, highlighting the importance of recognizing and managing potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An unusual case of checkpoint-inhibitor-induced pleuropericarditis. Suarez, ZK., Finke, AC., Hospedales, E., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10493109/

Advances in Immunotherapy for the Treatment of Cutaneous T ... Preliminary results from the phase 2 trial indicate global confirmed ORR of 22%, including skin in 35% and blood in 38% in a relapsed/refractory ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1936523323000220

A systematic review and meta-analysis of immune ... Primary mediastinal large B-cell lymphoma (PMBCL) also showed a favorable response, however, neither FL nor DLBCL had satisfactory results. DLBCL was the worst ...

3. aacrjournals.org aacrjournals.org/clincancerres/article/27/8/2190/672069/Phase-I-Study-of-the-CD47-Blocker-TTI-621-in

Phase I Study of the CD47 Blocker TTI-621 in Patients with ... The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). Results: Overall, 164 patients ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02362997

NCT02362997 | Pembrolizumab After ASCT for Hodgkin ... Blocking PD-1 with pembrolizumabmay restore an effective immune attack against the lymphoma cells. On this study, patients who undergo ASCT for R/R cHL, DLBCL ...

5. keytrudahcp.com keytrudahcp.com/efficacy/

Efficacy Data for KEYTRUDA® (pembrolizumab) The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%). In KEYNOTE⁠-⁠671, adverse reactions ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34627593/

Intralesional TTI-621, a novel biologic targeting the innate ... Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02890368

Trial of Intratumoral Injections of TTI-621 in Subjects With ... This is a multicenter, open-label, phase 1 study conducted to test intratumoral injections of TTI-621 in subjects that have relapsed and refractory ...

8. thelancet.com thelancet.com/journals/lanhae/article/PIIS2352-3026(21)00271-4/abstract

Intralesional TTI-621, a novel biologic targeting the innate ... This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.11508

Safety and clinical activity of TTI-621 in combination with ... Addition of TTI-621 to doxorubicin showed promising clinical activity and a favorable safety profile among pts with advanced LMS, including those with ...