HRO761 + Other Drugs for MSI-H Cancers

Recruiting at 37 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Novartis Pharmaceuticals

Disqualifiers: Cardiac disease, CNS tumor, HIV, others

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

Compensation: Varies

Number of Visits: 10

327 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, HRO761, both alone and with other medications, to determine its safety and effectiveness for people with certain advanced cancers that have specific genetic changes called MSI-H or dMMR. The trial aims to identify the best dose and assess its effectiveness when combined with pembrolizumab (an immunotherapy drug) or irinotecan (a chemotherapy drug). Suitable participants have advanced cancers that have not responded well to previous treatments and possess these specific genetic changes. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

A previous study showed that HRO761 can stop cancer cells from growing. However, this research remains in the early stages, so detailed safety information is limited. The main goal is to find the safest effective dose.

Researchers are testing HRO761 alone and with other drugs like pembrolizumab and irinotecan. Pembrolizumab has been safely used in people with certain types of cancer, so combining it with HRO761 aims to enhance its effects without adding significant risks. Irinotecan, another drug commonly used in cancer treatment, has a well-known safety record.

Although detailed information on how people handle HRO761 is not yet available, its testing suggests earlier lab studies showed some safety potential. This trial will provide more concrete information about its safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about HRO761 for MSI-H cancers because it introduces a novel approach to treatment. Unlike traditional treatments like chemotherapy, HRO761 can be combined with pembrolizumab, a known immunotherapy, potentially enhancing the immune system's ability to target cancer cells. Additionally, when paired with irinotecan, HRO761 might offer a new mechanism to inhibit tumor growth. These combinations could lead to more effective and personalized treatment options, providing new hope for patients with MSI-H cancers.

What evidence suggests that this trial's treatments could be effective for MSI-H cancers?

Research shows that HRO761 is a promising treatment for certain cancers with specific genetic changes known as MSI-H or dMMR. Lab studies have demonstrated that HRO761 effectively stops these cancer cells from growing by targeting a protein called WRN, which aids in cell repair and survival. In this trial, participants may receive HRO761 alone or with other treatments. One arm of the trial will test HRO761 with pembrolizumab, a current cancer treatment that has shown significant tumor reduction in some MSI-H cancers. Pembrolizumab has already improved outcomes in some of these cancer types. Another arm will explore the combination of HRO761 with irinotecan, although less information exists about this combination. The potential of HRO761 alone offers hope for its success in combination treatments. Overall, early research suggests that HRO761 could be helpful in treating these specific cancer types. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with advanced, inoperable or metastatic solid tumors that have specific DNA changes known as MSIhi or dMMR. They should have tried standard treatments without success and be physically capable of daily activities (ECOG ≤ 1). Some participants must have had immune therapy before, while others shouldn't. All need measurable disease and available tumor tissue samples.

Inclusion Criteria

I am willing to have a biopsy of my cancer, as per my doctor's advice.

I have tumor tissue samples from before starting the study treatment.

I have had chemotherapy or targeted therapy but not immune checkpoint inhibitors.

Exclusion Criteria

I have a major problem with my eyesight.

History of severe hypersensitivity reactions to any ingredient of study drug(s)

I do not have severe stomach or bowel problems that could affect drug absorption, except for having had my stomach removed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Different groups of people will be given different doses of HRO761 to understand how the body reacts to different doses of the drug and how well the drug acts against the cancer.

8 weeks

Approximately 8 visits (in-person)

Dose Optimization

Selected doses will be tested in more patients until a recommended dose(s) is found.

8 weeks

Approximately every 2 or 4 weeks thereafter

Dose Expansion

More people may be treated with HRO761 alone or together with pembrolizumab or irinotecan to further assess the study treatment effects against various types of MSIhi or dMMR cancers.

Up to 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• HRO761
• Irinotecan
• Tislelizumab

Trial Overview The study tests HRO761 alone or combined with tislelizumab (an immune checkpoint inhibitor) or irinotecan (a chemotherapy drug), to find the safest and most effective doses for treating cancers with MSIhi/dMMR alterations. The goal is to see how well HRO761 works against these cancers.

How Is the Trial Designed?

Group I: C: HRO761 + irinotecan Experimental Treatment 2 Interventions

phase Ib (Dose escalation and expansion)

Group II: B: HRO761 + pembrolizumab Experimental Treatment 2 Interventions

phase Ib (Dose escalation and expansion)

Group III: A: HRO761 single agent Experimental Treatment 1 Intervention

phase Ib (Dose finding (Escalation and Optimization) and expansion)

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

Microsatellite instability-high (MSI-H) gastric cancer is associated with specific characteristics such as female gender, advanced age, and positive PD-L1 expression, indicating a unique profile that may influence treatment strategies.

The combined positive score (CPS) of PD-L1 expression serves as an independent prognostic factor for MSI-H gastric cancer, while a 'diffuse-pattern' of PD-L1 expression is linked to more aggressive features like lymphatic-vascular invasion and may indicate worse outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Expression level and prognostic value of PD-L1 in microsatellite instability-high gastric cancer]. Wang, XY., Hu, YJ., Dong, K., et al.[2020]

Pembrolizumab therapy showed promising antitumor activity in patients with microsatellite instability-high (MSI-H) advanced gastric or gastroesophageal junction cancer, with a median progression-free survival of 17.8 months in the second-line treatment setting, significantly better than chemotherapy's 3.5 months.

The objective response rate for pembrolizumab was notably high, reaching 57.1% in the third-line treatment and 46.7% in the second-line treatment, indicating its potential as an effective treatment option for MSI-H tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials. Chao, J., Fuchs, CS., Shitara, K., et al.[2022]

In a study of 73 patients with high-level microsatellite instability (MSI-H) cancers, the overall five-year survival rate was 86%, indicating a generally favorable prognosis for these patients.

However, the prognosis varies significantly with cancer stage; for example, stage 4 MSI-H colorectal cancer patients had a much lower five-year survival rate of only 22.9%, suggesting that advanced disease may negate the initial survival advantage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical course and outcome of patients with high-level microsatellite instability cancers in a real-life setting: a retrospective analysis. Halpern, N., Goldberg, Y., Kadouri, L., et al.[2020]

In a study of 150 patients with non-familial colorectal cancer, 13.33% exhibited a high-frequency microsatellite instability (MSI-H) phenotype, which is associated with specific pathological features.

Key independent factors for identifying MSI-H non-familial colorectal cancer include poor differentiation, histological heterogeneity, Crohn's-like reaction, and the presence of tumor-infiltrating lymphocytes, with a high accuracy of 95.3% in detection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinicopathological features of non-familial colorectal cancer with high-frequency microsatellite instability. Peng, J., Xiao-ming, M., Jian-qiu, S., et al.[2019]

Mismatch repair deficiency (dMMR) leading to microsatellite instability-high (MSI-H) is a significant mechanism in 15% of colorectal cancers (CRCs), characterized by distinct features and better survival rates compared to other CRC types.

MSI-H CRCs do not respond well to standard chemotherapy but show promising responses to immunotherapy, with FDA-approved treatments like pembrolizumab and nivolumab, highlighting the importance of MSI testing in guiding treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Microsatellite Instability Testing in Management of Colorectal Cancer. Sun, BL.[2021]

Patients with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) tumors show a strong response to immune checkpoint inhibitors, leading to significantly improved outcomes.

Despite initial effectiveness, many patients develop resistance to these treatments, highlighting the need for new therapeutic strategies, which are currently being researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-agnostic drug development in dMMR/MSI-H solid tumors. Bhamidipati, D., Subbiah, V.[2023]

Microsatellite instability-high (MSI-H) stomach adenocarcinoma (STAD) tumors can be divided into two subgroups (MSI-H1 and MSI-H2), with the MSI-H1 subgroup showing immune suppression factors that may lead to poorer patient prognosis.

Understanding the genetic differences within MSI-H STAD tumors is crucial for improving risk assessment, prognosis, and treatment strategies for cancer patients, as not all MSI-H patients benefit from immune checkpoint-blockade therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival. Yang, Y., Shi, Z., Bai, R., et al.[2021]

Microsatellite-instability-high (MSI-H) cancers, associated with Lynch Syndrome, exhibit a high degree of genomic instability and a unique immune profile, making them responsive to immune checkpoint blockade therapies.

The treatment landscape for MSI-H cancers, particularly colorectal cancers, is evolving, with immune checkpoint inhibitors becoming a key strategy, although the overall treatment approach is still being defined.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The distinct clinical trajectory, metastatic sites, and immunobiology of microsatellite-instability-high cancers. Han, S., Chok, AY., Peh, DYY., et al.[2022]

Immune-checkpoint therapy targeting PD-1 has shown limited effectiveness in general colorectal cancer, but it demonstrates significant antitumor activity in a specific subset known as mismatch deficiency or microsatellite instability high (MSI-high) CRC.

Understanding the unique immunological characteristics of MSI-high CRC is essential for improving the success of immunotherapy, and ongoing clinical trials are exploring these targeted treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy Progress in Mismatch Repair-Deficient Colorectal Cancer and Future Therapeutic Challenges. Link, JT., Overman, MJ.[2017]

Citations

1. nature.com nature.com/articles/s41586-024-07350-y

Discovery of WRN inhibitor HRO761 with synthetic lethality ... HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0960894X25000502

Discovery of novel WRN inhibitors for treating MSI-H ... Accordingly, WRN is considered a potential therapeutic target in MSI-H cancers. HRO761, a non-covalent WRN inhibitor developed by Novartis, ...

3. novartis.com novartis.com/clinicaltrials/study/nct05838768

Study of HRO761 Alone or in Combination in Cancer ... The main purpose of the study is to evaluate the safety and tolerability of HRO761 and identify the recommended dose(s).

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05838768

NCT05838768 | Study of HRO761 Alone or in Combination ... The main purpose of the study is to evaluate the safety and tolerability of HRO761 and identify the recommended dose(s), i.e., the optimal safe and active ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12328481/

Targeting the Werner syndrome protein in microsatellite ... Preclinical studies have demonstrated the efficacy of HRO761 in both cell-derived xenograft and patient-derived xenograft (PDX) models, showing ...

6. fightcolorectalcancer.org fightcolorectalcancer.org/zh/clinical-trial/study-of-hro761-alone-or-in-combination-in-cancer-patients-with-specific-dna-alterations-called-microsatellite-instability-or-mismatch-repair-deficiency-2/

Clinical trial's patient recruitment status Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair Deficiency. ... MSI- ...

7. clin.larvol.com clin.larvol.com/trial-detail/NCT05838768

Study of HRO761 Alone or in Combination in Cancer ... Impact Score 7Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair ...