HRO761 + Other Drugs for MSI-H Cancers

Recruiting at 32 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

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called HRO761, which targets a protein that helps cancer grow. It is for patients with specific types of cancer that might respond better to this treatment. The study will find the best dose of HRO761 alone and with other drugs, and see how well it works.

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.

What data supports the effectiveness of the drug HRO761 + Other Drugs for MSI-H Cancers?

Research shows that MSI-H cancers, which have a lot of genetic changes, respond well to immune checkpoint inhibitors, a type of drug that helps the immune system attack cancer. However, many patients eventually stop responding to these drugs, so combining them with other treatments like HRO761 might offer better results. ^{1 2 3 4 5}

What makes the drug HRO761 unique for treating MSI-H cancers?

HRO761 is unique because it is being studied in combination with other drugs to potentially overcome resistance to single-agent immune checkpoint inhibitors, which are currently used for MSI-H cancers but can become less effective over time. ^{1 6 7 8 9}

Eligibility Criteria

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.

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

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

Timeline

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

References

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

Tumor-agnostic drug development in dMMR/MSI-H solid tumors. [2023]

2. United States 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. [2022]

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

Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The distinct clinical trajectory, metastatic sites, and immunobiology of microsatellite-instability-high cancers. [2022]

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

Immunotherapy Progress in Mismatch Repair-Deficient Colorectal Cancer and Future Therapeutic Challenges. [2017]

6. New Zealand 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. [2020]

7. China pubmed.ncbi.nlm.nih.gov

Clinicopathological features of non-familial colorectal cancer with high-frequency microsatellite instability. [2019]

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

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

9. China pubmed.ncbi.nlm.nih.gov

[Expression level and prognostic value of PD-L1 in microsatellite instability-high gastric cancer]. [2020]