LB101 for Solid Tumors

Recruiting at 7 trial locations

Overseen By Centessa Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Centessa Pharmaceuticals (UK) Limited

Must not be taking: Immunosuppressants, Glucocorticoids, Live vaccines, others

Disqualifiers: Autoimmune diseases, HIV, Hepatitis, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment called LB101 on its own in patients with advanced solid tumors. The goal is to see if LB101 is safe, can be tolerated by patients, and if it helps in controlling or shrinking the tumors. The study will also look at how the body processes the treatment and the immune response to it. New studies are looking into different types of treatments for various cancers. Previous concerns about safety had slowed progress, but recent research suggests that new versions of these treatments may be safer and more effective when used with other therapies.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot participate if you have received immunosuppressive drugs within 7 days before starting LB101 or if you have ongoing side effects from previous therapies. It's best to discuss your current medications with the trial team.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have taken immunosuppressive drugs within 7 days before starting the trial or if you have ongoing side effects from previous treatments.

What data supports the idea that LB101 for Solid Tumors is an effective treatment?

The available research shows that treatments targeting PD-L1, like LB101, can help the immune system fight cancer by blocking the PD-L1/PD-1 axis, which is a way cancer cells avoid being attacked. While some patients respond well to these treatments, others do not, due to factors like low immune cell presence in tumors. However, using PD-L1 targeting treatments as carriers for toxic substances has shown promise in eliminating cancer cells. This suggests that LB101 could be effective, especially if it can overcome the challenges faced by other similar treatments. ^{1 2 3 4 5}

What data supports the effectiveness of the drug LB101 for solid tumors?

Research shows that blocking the PD-L1 protein, which is targeted by LB101, can help the immune system fight cancer cells more effectively. Similar treatments that target PD-L1 have been approved and used successfully in various cancers, suggesting potential effectiveness for LB101. ^{1 2 3 4 5}

What safety data is available for LB101 treatment for solid tumors?

The provided research does not contain specific safety data for LB101, PD-L1xCD47 LockBody, or related treatments. The articles discuss PD-L1/PD-1 blockade strategies, bispecific T-cell engagers, and PD-L1 targeting antibodies, but do not provide safety data for LB101 or PD-L1xCD47 LockBody specifically. ^{1 2 3 5 6}

What safety data exists for LB101 or PD-L1xCD47 LockBody in humans?

The research articles provided do not contain specific safety data for LB101 or PD-L1xCD47 LockBody in humans. ^{1 2 3 5 6}

Is the drug LB101 (PD-L1xCD47 LockBody) a promising treatment for solid tumors?

Yes, LB101 is a promising treatment for solid tumors. It targets PD-L1, a protein that helps tumors hide from the immune system, and CD47, which is involved in preventing the immune system from attacking cells. By blocking these proteins, LB101 can help the immune system recognize and attack cancer cells more effectively. This approach has shown potential in improving the body's ability to fight tumors. ^{1 5 7 8 9}

What makes the drug LB101 unique for treating solid tumors?

LB101 is unique because it combines two mechanisms: targeting PD-L1, a protein that helps tumors evade the immune system, and CD47, which is often used by cancer cells to avoid being destroyed by immune cells. This dual action aims to enhance the immune system's ability to attack cancer cells more effectively than treatments targeting only one of these pathways. ^{1 5 7 8 9}

Eligibility Criteria

Adults (18+) with advanced solid tumors, including specific types of lung, head and neck, cervical, ovarian cancers. Must have tried checkpoint inhibitors previously or have no standard treatment options left. Participants need to be in relatively good health with a life expectancy of at least 12 weeks and weigh over 40 kg. They must agree to use two effective contraception methods if applicable and provide tissue samples.

Inclusion Criteria

Participants with life expectancy >= 12 weeks

My blood counts are within a healthy range.

I have a stored sample of my tumor tissue.

Exclusion Criteria

I have not received immunotherapy for my cancer.

My advanced disease worsened within 6 months after finishing my initial cancer treatment.

I am currently on IV medication for an infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Part 1a)

Participants receive LB101 once every 2 weeks in a 28-day cycle to determine safe dose levels

28 days

2 visits (in-person)

Dose Optimization (Part 1b)

Participants receive optimized dose levels and/or schedules deemed safe from Part 1a

Varies based on dose schedule

Dose Expansion (Part 2)

Further evaluation of safety, efficacy, tolerability, pharmacokinetics, and immune response of LB101

Varies based on results from Part 1

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• LB101

Trial Overview The trial is testing LB101 as a solo treatment for various advanced solid tumors to see how safe it is and if it works. It involves people who've already had certain treatments like immune checkpoint inhibitors or those without other treatment choices.

Participant Groups

Group I: LB101 Experimental Treatment 1 Intervention

Part 1 Part 1a participants will receive LB101 once every 2 weeks (Q2W) (28-day cycle), with a preliminary plan for 6 sequential dose levels. Part 1b will be a dose optimization and will include \>1 dose levels and/or dose schedules that have been deemed safe and tolerable in Part 1a. Part 2 Dose regimen(s) for participants in Part 2 will be based on the results of Part 1.

LB101 is already approved in United States for the following indications:

Approved in United States as LB101 for:

• None approved; currently in Phase 1/2a clinical trial for advanced solid tumors

Who Is Running the Clinical Trial?

Centessa Pharmaceuticals (UK) Limited

Lead Sponsor

Trials

2

Recruited

100+

LockBody Therapeutics Ltd

Industry Sponsor

Trials

1

Recruited

30+

Findings from Research

The novel bispecific T cell engager (BiTE) PD-L1×CD3 nanobody effectively activates T cells to produce important immune signals (TNF-α and IFN-γ) in a dose-dependent manner, with an IC50 value of 4.208 μg/mL.

BiTE PD-L1×CD3 Nb demonstrated significant cytotoxic activity against melanoma cells, particularly those with high PD-L1 expression, indicating its potential as a targeted therapy for advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A PD-L1xCD3 bispecific nanobody as a novel T-cell engager in treating PD-L1 overexpression melanoma. Li, B., Wang, S., Shan, B., et al.[2023]

The PD-L1/PD-1 axis is a crucial immune checkpoint mechanism that cancer cells exploit to evade immune detection, making it a key target for cancer immunotherapy with FDA-approved anti-PD-L1 antibodies like atezolizumab, durvalumab, and avelumab.

While anti-PD-L1 antibodies show promise in clinical trials, their effectiveness can be limited by factors such as low T cell infiltration in tumors; thus, using these antibodies as carriers for toxic payloads (immunoconjugates) may enhance their therapeutic potential against PD-L1 expressing cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-L1 immunoconjugates for cancer therapy: Are available antibodies good carriers for toxic payload delivering? Zanello, A., Bortolotti, M., Maiello, S., et al.[2022]

The PD-1 pathway plays a crucial role in suppressing T-cell activation, which is important for maintaining immune tolerance, but its high expression in tumors contributes to a suppressive environment that promotes cancer growth.

Blocking the PD-1 axis using PD-L2 fusion proteins or monoclonal antibodies has been clinically tested across various tumor types, showing promise in enhancing antitumor immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Cancer Immunotherapy with PD-1/PD-L1 Blockade. Zheng, P., Zhou, Z.[2022]

In a study of 144 breast cancer patients, PD-L1 expression was found more frequently in triple negative breast cancer (TNBC) patients, suggesting that these patients may benefit from PD-L1 inhibition therapy due to their resistance to standard chemotherapy.

The study found no significant difference in soluble PD-L1 serum levels between breast cancer patients and healthy women, indicating that low serum levels of sPD-L1 are unlikely to interfere with PD-L1 inhibition therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 expression in tumor lesions and soluble PD-L1 serum levels in patients with breast cancer: TNBC versus TPBC. Yazdanpanah, P., Alavianmehr, A., Ghaderi, A., et al.[2021]

The newly developed PET tracers [18F]AlF-NOTA-ZPD-L1_4 and [68Ga]NOTA-ZPD-L1_4 showed significantly higher accumulation in PD-L1 positive tumors compared to PD-L1 negative tumors, indicating improved targeting for monitoring PD-L1 expression during immunotherapy.

Both tracers demonstrated favorable biodistribution in rhesus monkeys, with fast kidney clearance and low liver background, suggesting they are suitable for same-day clinical imaging of PD-L1, although high kidney accumulation may limit the radioactive doses used in repeated studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Evaluation and Dosimetry Estimate for a High Affinity Affibody PET Tracer Targeting PD-L1. Rubins, DJ., Meng, X., McQuade, P., et al.[2021]

In a case report involving three patients with renal cell carcinoma and melanoma, all experienced disease progression after receiving a second PD-1 inhibitor (nivolumab) following initial treatment with a PD-1/PD-L1 inhibitor, indicating limited efficacy of sequential PD-1 therapies.

The authors recommend that clinicians avoid using multiple PD-1/PD-L1 inhibitors sequentially outside of clinical trials until more data is available, highlighting the need for further research to understand the mechanisms of resistance and to validate the safety and efficacy of these treatments in later lines of therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: a case series. Martini, DJ., Lalani, AA., Bossé, D., et al.[2018]

The study successfully developed a Nanobody-based probe for imaging human PD-L1 expression using positron emission tomography, achieving over 95% radiochemical purity with two different radiolabeling strategies.

Both site-specific and random conjugation methods for labeling the Nanobody showed effective tumor targeting in vivo, indicating that random lysine-conjugation is a viable option for clinical applications despite potential concerns about affinity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-human PD-L1 Nanobody for Immuno-PET Imaging: Validation of a Conjugation Strategy for Clinical Translation. Bridoux, J., Broos, K., Lecocq, Q., et al.[2021]

A new noninvasive imaging technique using radiolabeled antibodies can effectively determine PD-L1 expression in tumors, which is crucial for selecting patients who are likely to benefit from anti-PD-1/PD-L1 therapies.

The study demonstrated that the radiolabeled antibody (111)In-PD-L1.3.1 specifically accumulates in tumors with high PD-L1 expression, allowing for better patient stratification and monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Imaging of Tumor PD-L1 Expression Using Radiolabeled Anti-PD-L1 Antibodies. Heskamp, S., Hobo, W., Molkenboer-Kuenen, JD., et al.[2021]

A novel PD-L1-binding affibody (M1) was developed using mRNA display, demonstrating low nanomolar affinity for both human and mouse PD-L1, which is crucial for potential diagnostic applications.

The M1 affibody effectively inhibited PD-L1:PD-1 signaling in a cell-based assay and showed significant tumor uptake in vivo, indicating its potential as a molecular imaging probe in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Directed Evolution of PD-L1-Targeted Affibodies by mRNA Display. Grindel, BJ., Engel, BJ., Ong, JN., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

A PD-L1xCD3 bispecific nanobody as a novel T-cell engager in treating PD-L1 overexpression melanoma. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-PD-L1 immunoconjugates for cancer therapy: Are available antibodies good carriers for toxic payload delivering? [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Human Cancer Immunotherapy with PD-1/PD-L1 Blockade. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

PD-L1 expression in tumor lesions and soluble PD-L1 serum levels in patients with breast cancer: TNBC versus TPBC. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

In Vivo Evaluation and Dosimetry Estimate for a High Affinity Affibody PET Tracer Targeting PD-L1. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: a case series. [2018]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-human PD-L1 Nanobody for Immuno-PET Imaging: Validation of a Conjugation Strategy for Clinical Translation. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Noninvasive Imaging of Tumor PD-L1 Expression Using Radiolabeled Anti-PD-L1 Antibodies. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Directed Evolution of PD-L1-Targeted Affibodies by mRNA Display. [2023]