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

Novartis

Status and phase: Enrolling; Phase 1

Conditions: MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal Cancers

Treatments: Biological: pembrolizumab; Drug: HRO761; Drug: irinotecan

Study type: Interventional

Funder types: Industry

Identifiers

NCT05838768

2022-502314-93-00 (Registry Identifier)

CHRO761A12101

Details and patient eligibility

About

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 dose of HRO761 alone or in combination with pembrolizumab or irinotecan that can be given to patients who have cancers with specific molecular alterations called MSIhi (Microsatellite Instability-high) or dMMR (Mismatch Repair Deficient) that might work best to treat these specific cancer types and to understand how well HRO761 is able to treat those cancers.

Full description

The new drug being tested in the study, HRO761, is an oral drug that acts on a protein called Werner (WRN), which may contribute to cancer growth. By acting on WRN, HRO761 may be able to stop the growth of the cancer.

This is the first time HRO761 is given to patients and the first time HRO761 is used in combination with pembrolizumab or irinotecan.

Pembrolizumab and irinotecan are drugs approved in several countries and used as standard treatment for certain types of cancer (e.g., colon cancer and small cell lung cancer).

This research study will consist of various treatment arms to investigate HRO761 as single agent and in the combinations.

For HRO761 single agent, the research will be done in two parts. The first part is called "dose escalation" and the second part is called "dose optimization". In the dose escalation part, 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. During the dose optimization part, the selected doses will be tested in more patients until a recommended dose(s) is found.

The combinations of HRO761 with pembrolizumab or irinotecan also will be tested in a dose escalation part to find the recommended doses of HRO761 in these combinations.

Once the recommended doses are determined, 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. This part is called dose expansion.

For this research, a number of blood and tissue samples will be collected during the study. Patients may be asked to come approximately 8 times to the clinic during the first 8 weeks and approximately every 2 or 4 weeks thereafter.

Patients will be in the study as long as their study doctor believes that they may be benefiting from the study treatment, unless the patient decides to stop study treatment.

Enrollment: 327 estimated patients

Sex: All

Ages: 18 to 100 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion criteria:

• Patients with advanced unresectable or metastatic MSIhi or MMR deficient (dMMR) solid tumors who have progressed after or are intolerant to prior standard therapy.

  • Arm A and C: Patients must have progressed on the most recent therapy for advanced disease including one prior line of immune checkpoint inhibitor therapy.
  • Arm B: Patients should have received prior chemotherapy or targeted therapy, and patients should have received prior immune checkpoint inhibitor or should be expected to benefit from immune checkpoint inhibitor therapy.

• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1

• Measurable disease as determined by RECIST version 1.1

• HRO761 s.a. (Arm A) dose finding only: Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy at screening, and during therapy on the study. A biopsy from the same lesion is preferred if safe and medically feasible. Exceptions may be considered after documented discussion with Novartis.

• All patients (Arm A, B and C) will have available archival tumor tissue obtained prior to study treatment initiation (in addition to newly obtained tumor biopsy at screening for Arm A), to allow retrospective MSIhi/dMMR status confirmation.

Key Exclusion criteria:

• Impaired cardiac function or clinically significant cardiac disease
• Clinically significant eye impairment
• Patients with a primary Central Nervous System (CNS) tumor or tumor metastatic to the CNS
• Human Immunodeficiency Virus (HIV) infection
• Active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Tuberculosis infection. Patients whose disease is controlled under antiviral therapy should not be excluded.
• History of severe hypersensitivity reactions to any ingredient of study drug(s)
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., severe ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection), except for prior gastrectomy.

Other protocol-defined inclusion/exclusion criteria may apply

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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327 participants in 3 patient groups

A: HRO761 single agent

Experimental group

Description:

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

Treatment:

Drug: HRO761

B: HRO761 + pembrolizumab

Experimental group

Description:

phase Ib (Dose escalation and expansion)

Treatment:

Drug: HRO761

Biological: pembrolizumab

C: HRO761 + irinotecan

Experimental group

Description:

phase Ib (Dose escalation and expansion)

Treatment:

Drug: irinotecan

Drug: HRO761