HST-1011 + Anti-PD1 Antibody for Advanced Cancer

Not currently recruiting at 15 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a potential new treatment for individuals with advanced solid tumors, including certain types of ovarian, anal, rectal, and prostate cancers. The study examines the effectiveness of a new drug, HST-1011 (a CBL-B inhibitor), both alone and in combination with cemiplimab (an anti-PD1 antibody). It targets those whose cancer has returned or did not respond to existing treatments. Participants must have at least one measurable tumor and should not have active autoimmune diseases or require regular steroid treatment. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

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

Research has shown that HST-1011 is generally safe when used alone. In early studies, patients taking HST-1011 did not experience severe side effects that required stopping the treatment, even at higher doses. Most side effects were mild and manageable.

When combined with cemiplimab (a type of immune therapy), studies have not identified any major safety issues. Early results are promising, with no significant negative effects reported. Cemiplimab's use in other treatments further supports its safety.

Overall, these findings suggest that HST-1011, whether used alone or with cemiplimab, is unlikely to cause serious harm, with most side effects being mild. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about HST-1011 because it represents a novel approach to treating advanced cancer. Unlike standard treatments, which often focus on directly attacking cancer cells, HST-1011 is designed to work alongside cemiplimab, an anti-PD1 antibody, to enhance the body's immune response against cancer. This combination aims to bolster the immune system's ability to recognize and destroy cancer cells more effectively. By potentially offering a new mechanism of action, this treatment could provide hope for patients who have not responded well to current therapies.

What evidence suggests that this trial's treatments could be effective for advanced cancer?

Research has shown that HST-1011, a new treatment, may aid in treating advanced solid tumors by boosting the body's immune system to fight cancer more effectively. Early results suggest it can significantly enhance the body's ability to combat tumors. In this trial, some participants will receive HST-1011 alone, while others will receive it with cemiplimab, another cancer-fighting drug. This combination aims to assist patients who haven't responded well to other treatments. Initial findings are promising, indicating manageable side effects and potential improvement in cancer treatment. Although still under testing, the early results are hopeful. ^{1 3 4 6 7}

Who Is on the Research Team?

Alison O'Neill, MD

Principal Investigator

HotSpot Therapeutics, Inc

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)02569-9/fulltext

991O First-in-human (FIH) phase I data of HST-1011, an ... All HST-1011 related TEAEs were clinically manageable, and only 1 patient discontinued therapy for patient preference. Translational analyses showed dose- ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05662397

A Study of HST-1011 Given as Monotherapy and in ... 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 ...

3. aacrjournals.org aacrjournals.org/cancerres/article/83/8_Supplement/CT251/725545/Abstract-CT251-Phase-1-2-study-of-HST-1011-an-oral

Abstract CT251: Phase 1/2 study of HST-1011, an oral CBL-B ... HST-1011 is a novel, potent, selective, orally bioavailable allosteric small molecule CBL-B inhibitor that has been shown to robustly increase anti-tumor ...

4. targetedonc.com targetedonc.com/view/phase-1-2-trial-of-hst-1011-begins-dosing-patients-with-advanced-solid-tumors

Phase 1/2 Trial of HST-1011 Begins Dosing Patients With ... The first patient has been dosed with HST-1011 in a phase 1/2 trial (NCT05662397) evaluating the agent in patients with advanced solid tumors.

5. hotspotthera.com hotspotthera.com/wp-content/uploads/2024/09/PRESENTATION-HotSpot-ESMO-2024-First-in-Human-FIH-Phase-1-Data-of-HST-1011-an-Oral-CBL-B-Inhibitor-in-Patients-with-Advanced-Solid-Tumors-.pdf

First-in-Human (FIH) Phase 1 Data of HST-1011, an Oral ... First-in-Human (FIH) Phase 1 Data of. HST-1011, an Oral CBL-B Inhibitor, in. Patients with Advanced Solid Tumors. SOLAR1 Clinical Trial, NCT05662397. Rachel E ...

6. hotspotthera.com hotspotthera.com/press_release/hotspot-therapeutics-presents-first-in-human-phase-1-clinical-data-on-its-novel-cbl-b-inhibitor-hst-1011-at-esmo-congress-2024/

HST-1011 showed an encouraging early clinical ... HST-1011 was generally well tolerated across a range of twice-weekly doses, with no dose-limiting toxicities. The most frequent adverse events ...

7. ir.nurixtx.com ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-reports-new-clinical-data-first-class-oral

Press releases Nurix Therapeutics Reports New Clinical Data from First-in-Class Oral CBL-B Inhibitor, NX-1607, Demonstrating Single-Agent Activity Across ...