HST-1011 + Anti-PD1 Antibody for Advanced Cancer

Recruiting at 14 trial locations

Overseen By Alison O'Neill, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: HotSpot Therapeutics, Inc

Must not be taking: Steroids, others

Disqualifiers: Autoimmune disease, CNS disease, others

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

Compensation: Varies

Number of Visits: Unknown

77 Participants Needed

Trial Summary

Do I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take medications that might interact with HST-1011.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications, but you cannot take medications that might interact with HST-1011. It's best to discuss your current medications with the trial team.

What data supports the idea that HST-1011 + Anti-PD1 Antibody for Advanced Cancer is an effective treatment?

The available research shows that targeting Cbl-b, a protein that usually limits immune cell activity, can enhance the body's ability to fight cancer. Studies indicate that when Cbl-b is inhibited, immune cells become more active and effective against tumors. This effect is even stronger when combined with anti-PD1 antibodies, which help the immune system recognize and attack cancer cells. In experimental models, this combination has led to better tumor control and regression. This suggests that HST-1011 + Anti-PD1 Antibody could be a promising treatment for advanced cancer by boosting the immune system's response to tumors. ^{1 2 3 4 5}

What evidence supports the effectiveness of the drug HST-1011 + Anti-PD1 Antibody for Advanced Cancer?

Research suggests that targeting Cbl-b, a protein involved in immune regulation, can enhance the body's immune response against tumors. Studies show that inhibiting Cbl-b can improve the effectiveness of treatments like anti-PD1 antibodies, which are used to help the immune system attack cancer cells. ^{1 2 3 4 5}

What safety data exists for HST-1011 + Anti-PD1 Antibody treatment?

The safety data for Anti-PD1 antibodies, such as Cemiplimab (Libtayo), includes reports of immune-mediated toxicities and specific adverse events like hepatitis B reactivation. These events can lead to treatment delays or discontinuation. Additionally, repeated administration of PD-1/PD-L1 antibodies in preclinical models has shown potential for fatal hypersensitivity reactions, although these findings may not directly translate to human trials. The safety profile of PD-1 blockade is generally considered manageable, but it requires careful monitoring for immune-related adverse effects. ^{6 7 8 9 10}

What safety data exists for HST-1011 + Anti-PD1 Antibody treatment?

Anti-PD-1 therapies, like those used in HST-1011 + Anti-PD1 Antibody treatment, have been associated with immune-related side effects, including the reactivation of hepatitis B in some cancer patients. Additionally, in animal studies, repeated administration of PD-1 antibodies led to severe allergic reactions, although this has not been observed in human trials. ^{6 7 8 9 10}

Is the drug HST-1011 a promising treatment for advanced cancer?

HST-1011, when combined with an anti-PD1 antibody, is a promising treatment for advanced cancer because it aims to boost the body's immune response against tumors. This combination can potentially enhance the effectiveness of the immune system in recognizing and fighting cancer cells, offering hope for better outcomes in patients with advanced cancer. ^{11 12 13 14 15}

What makes the drug HST-1011 + Anti-PD1 Antibody unique for advanced cancer?

HST-1011 combined with an Anti-PD1 Antibody is unique because it targets a specific protein called CBL-B, which is involved in regulating the immune system's response to cancer. This approach aims to enhance the body's natural ability to fight tumors by potentially overcoming limitations seen in other treatments that only target PD-1 or PD-L1 pathways. ^{11 12 13 14 15}

What is the purpose of this trial?

This is a Phase 1/2 study of HST-1011, a CBL-B inhibitor, being developed for the treatment of patients with advanced solid tumors, who relapsed while on or are refractory to approved anti-PD(L)1 therapies or other standard of care.

Research Team

Alison O'Neill, MD

Principal Investigator

HotSpot Therapeutics, Inc

Eligibility Criteria

This trial is for adults with advanced solid tumors who have not responded to anti-PD(L)1 therapies or other standard treatments. Participants must be able to undergo biopsies, understand the study requirements, and have at least one measurable tumor lesion. They cannot join if they have active infections, untreated brain metastases, conditions affecting drug absorption, suspected COVID-19 infection, or are on medications that could interact with HST-1011.

Inclusion Criteria

I am fully active or can carry out light work.

Patient has signed and dated ICF

Patient has at least 1 measurable non-central nervous system lesion per RECIST 1.1

Exclusion Criteria

I have untreated brain metastases causing symptoms.

I am currently on long-term steroids for an autoimmune disease or another condition.

Patient has previously participated in a clinical study evaluating a CBL-B inhibitor

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive HST-1011 as monotherapy or in combination with cemiplimab in dose escalation and optimization parts

12 months

Phase 2 Treatment

Evaluation of the preliminary antitumor activity of HST-1011 in combination with anti-PD(L)1 antibody or other standard of care therapies

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Cemiplimab
• HST-1011

Trial Overview The study tests HST-1011 alone and combined with Cemiplimab in patients whose solid tumors didn't improve after anti-PD(L)1 therapy or standard care. It's a Phase 1/2 trial aiming to find out how safe and effective these treatments are when others fail.

Participant Groups

Group I: HST-1011 Monotherapy Dose Optimization (Part A2) Experimental Treatment 1 Intervention

Evaluation of HST-1011 monotherapy dose/dose regimen.

Group II: HST-1011 Monotherapy Dose Escalation (Part A1) Experimental Treatment 1 Intervention

Multiple dose levels of HST-1011 to be evaluated.

Group III: HST-1011 Dose Optimization in Combination with Cemiplimab (Part B2) Experimental Treatment 2 Interventions

Evaluation of HST-1011 in combination with cemiplimab.

Group IV: HST-1011 Dose Escalation in Combination with cemiplimab (Part B1) Experimental Treatment 2 Interventions

Multiple dose levels of HST-1011 to be evaluated in combination with cemiplimab.

Who Is Running the Clinical Trial?

HotSpot Therapeutics, Inc

Lead Sponsor

Trials

1

Recruited

80+

Findings from Research

Cbl-b deficiency in T cells and NK cells leads to resistance against PD-L1/PD-1-mediated suppression, enhancing their ability to respond to tumors, as shown in both in vitro and in vivo studies.

Targeting Cbl-b in cancer immunotherapy could provide a strategy to overcome multiple immune checkpoints, potentially improving antitumor immunity without the need for additional treatments like anti-PD-1 antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cbl-b Deficiency Mediates Resistance to Programmed Death-Ligand 1/Programmed Death-1 Regulation. Fujiwara, M., Anstadt, EJ., Clark, RB.[2019]

Cbl-b is a key regulator in the immune response that can create an immunosuppressive environment in tumors, and targeting it with novel inhibitors has shown promise in reversing this suppression and enhancing T cell activity, leading to tumor regression in experimental models.

Recent advancements in drug development techniques, such as CRISPR and allosteric targeting, have made it possible to effectively target Cbl-b, potentially improving outcomes for patients who do not respond to traditional anti-PD1 therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Cbl-b in cancer immunotherapy. Augustin, RC., Bao, R., Luke, JJ.[2023]

c-Cbl, an E3 ubiquitin ligase, plays a crucial role in regulating the tumor microenvironment by suppressing the immune checkpoint receptor PD-1, which is important for immune responses in colorectal cancer (CRC).

In experiments with CRC xenografts, c-Cbl deficiency led to increased tumor growth and higher PD-1 levels in immune cells, indicating that c-Cbl's ability to destabilize PD-1 through ubiquitination is a key mechanism in its tumor-suppressive activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth. Lyle, C., Richards, S., Yasuda, K., et al.[2021]

Knocking down the Cbl-b protein in tumor-reactive CD8(+) T cells improved their survival and function, enhancing the effectiveness of adoptive immunotherapy in mice with leukemia.

This approach allowed T cells to effectively eliminate tumors without needing additional IL-2 treatment, suggesting a safer and more targeted method for boosting T cell responses in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice. Stromnes, IM., Blattman, JN., Tan, X., et al.[2022]

Cbl-b is a crucial negative regulator of T-cell activation, and its deficiency leads to hyperactive CD8(+) T cells that can effectively reject tumors, suggesting a potential for enhanced anti-tumor immunity.

Cbl-b-deficient T cells show resistance to immunosuppressive factors like TGF-β, indicating that targeting Cbl-b could improve the efficacy of cancer immunotherapy, especially in adoptive T-cell transfer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Releasing the brake: targeting Cbl-b to enhance lymphocyte effector functions. Wallner, S., Gruber, T., Baier, G., et al.[2021]

In a retrospective study of 7 patients with relapsed/refractory classical Hodgkin lymphoma (cHL) who received PD-1 blockade after prior treatment with avelumab (a PD-L1 blocker), 86% showed a positive response, indicating that this treatment sequence can be effective.

The median duration of response to PD-1 blockade was 26.4 months, with a median time to progression of 22.2 months, and only one patient experienced a mild immune-related adverse event, suggesting that this approach is safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 Blockade After Avelumab in Relapsed/Refractory Classical Hodgkin Lymphoma. Thiruvengadam, SK., Mei, MG., Godfrey, J., et al.[2022]

A retrospective analysis of adverse events related to PD-1/PD-L1 inhibitors revealed a significant association between Pembrolizumab and hepatitis B reactivation (HBVr), with a reporting odds ratio of 2.32, indicating a higher risk compared to other treatments.

No cases of HBVr were reported with Ipilimumab or Avelumab, suggesting that not all immune checkpoint inhibitors carry the same risk, highlighting the need for further prospective studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. Burns, EA., Muhsen, IN., Anand, K., et al.[2023]

Brentuximab vedotin (BV) and PD-1-blocking antibodies (nivolumab and pembrolizumab) have significantly changed the treatment approach for classical Hodgkin lymphoma (cHL), especially for patients with relapsed or refractory cases.

The article provides practical guidance on integrating these targeted immunotherapies into clinical practice, supported by a review of relevant studies, highlighting the need for optimized treatment strategies as these therapies are increasingly used earlier in the disease course.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How I incorporate novel agents into the treatment of classical Hodgkin lymphoma. Epperla, N., Herrera, AF.[2021]

Classical Hodgkin lymphoma (cHL) shows a high response rate of about 70% to PD-1 inhibitors due to common genetic alterations in 9p24.1 that lead to constant expression of PD-1 ligands, making it uniquely sensitive to this treatment.

In contrast, most non-Hodgkin lymphomas (NHLs) do not have these genetic alterations and are generally less responsive to PD-1 blockade, although certain subtypes like primary mediastinal B cell lymphoma may still benefit, prompting ongoing research into combination therapies and other immune checkpoint targets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checkpoint blockade in Hodgkin and non-Hodgkin lymphoma. Merryman, RW., Armand, P., Wright, KT., et al.[2022]

In a study using the 4T1 mammary carcinoma model, repeated administration of PD-1 and PD-L1 monoclonal antibodies led to rapid and fatal hypersensitivity reactions in tumor-bearing mice, highlighting a significant safety concern with these treatments.

The adverse effects were linked to the accumulation of specific antibodies and neutrophils, but these toxicities could be mitigated by combining PD-1 blockade with the HSP90 inhibitor ganetespib, suggesting a potential strategy to enhance safety in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer. Mall, C., Sckisel, GD., Proia, DA., et al.[2021]

The study developed a bispecific antibody (BsAb) targeting both PD-L1 and B7-H3, which showed improved stability and effectiveness in activating T cells and inducing tumor cell death compared to traditional monoclonal antibodies.

In a humanized tumor model, the BsAb demonstrated enhanced antitumor activity over monotherapies and some combination therapies, suggesting it may be a more effective treatment for tumors expressing both PD-L1 and B7-H3.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities. Li, HY., Chen, YL., Deng, XN., et al.[2023]

The combination of PD-1/PD-L1 and CTLA-4 inhibitors significantly improves objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in patients with advanced lung cancer, based on a review of six studies.

While the incidence of severe adverse events (grade ≥3) was lower than in control groups, it was still notable, indicating that while the treatment is generally tolerable, monitoring for side effects remains important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of PD-1/PD-L1 plus CTLA-4 antibodies ± other therapies in lung cancer: a systematic review and meta-analysis. Shen, X., Huang, S., Xiao, H., et al.[2023]

Therapeutic antibodies known as checkpoint inhibitors, which target PD-1 and CTLA-4, can enhance the body's anti-tumor immune response but are expensive and may cause severe side effects, affecting only a small percentage of patients.

Identifying biomarkers, such as tumor PD-L1 expression and tumor mutational burden, is crucial for predicting which patients are likely to respond to these treatments, helping to optimize their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers of response to PD-1 pathway blockade. Li, H., van der Merwe, PA., Sivakumar, S.[2022]

Two new mouse anti-human PD-L1 monoclonal antibodies, 10E10 and 2H11, were developed, with 10E10 showing the ability to activate immune cells and inhibit T-cell apoptosis caused by tumor-associated PD-L1.

The study found that PD-L1 is expressed in human gastric carcinoma but not in normal tissues, suggesting its potential as a prognostic marker for gastric cancer and a target for immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 expression analysis in gastric carcinoma tissue and blocking of tumor-associated PD-L1 signaling by two functional monoclonal antibodies. Sun, J., Xu, K., Wu, C., et al.[2020]

Checkpoint-blocking antibodies, like ipilimumab, enhance the immune system's ability to recognize and eliminate tumors by blocking the CTLA-4 receptor, which normally inhibits T-cell activation.

The review discusses the clinical development of CTLA-4 blocking antibodies, highlighting their effectiveness in cancer treatment, associated toxicities, and the exploration of biomarkers to predict patient responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity, Toxicity, Biomarkers, and Future Development of CTLA-4 Checkpoint Antagonists. Callahan, MK., Wolchok, JD.[2017]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Cbl-b Deficiency Mediates Resistance to Programmed Death-Ligand 1/Programmed Death-1 Regulation. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Targeting Cbl-b in cancer immunotherapy. [2023]

3. England pubmed.ncbi.nlm.nih.gov

c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth. [2021]

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

Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice. [2022]

5. Egypt pubmed.ncbi.nlm.nih.gov

Releasing the brake: targeting Cbl-b to enhance lymphocyte effector functions. [2021]

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

PD-1 Blockade After Avelumab in Relapsed/Refractory Classical Hodgkin Lymphoma. [2022]

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

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. [2023]

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

How I incorporate novel agents into the treatment of classical Hodgkin lymphoma. [2021]

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

Checkpoint blockade in Hodgkin and non-Hodgkin lymphoma. [2022]

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

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer. [2021]

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

Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of PD-1/PD-L1 plus CTLA-4 antibodies ± other therapies in lung cancer: a systematic review and meta-analysis. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Biomarkers of response to PD-1 pathway blockade. [2022]

14. England pubmed.ncbi.nlm.nih.gov

PD-L1 expression analysis in gastric carcinoma tissue and blocking of tumor-associated PD-L1 signaling by two functional monoclonal antibodies. [2020]

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

Clinical Activity, Toxicity, Biomarkers, and Future Development of CTLA-4 Checkpoint Antagonists. [2017]