An Open-label, Multi-center Phase I/Ib Dose Finding and Expansion Study of HRO761 as Single Agent and in Combinations in Patients With Microsatellite Instability-High or Mismatch Repair Deficient Advanced Solid Tumors.
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Study Summary
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 tislelizumab 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. To assess the safety, tolerability and preliminary anti-tumor activity in patients with MSI colorectal cancer and other MSI solid tumors. To investigate HRO761 in pts with MSI-H/dMMR advanced solid tumors. Key aims are to assess the safety/tolerability, recommended dose, and antitumor activity of HRO761.
The aim of this study was to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of HRO761 as monotherapy (sa) or in combination with the anti-PD-1 antibody tislelizumab or the topoisomerase inhibitor irinotecan. The primary objective of the dose-finding phase was to determine a safe and tolerable dose and dosing regimen, and to establish a recommended dose (RD) for HRO761 monotherapy or in combination therapy. The dose-finding phase for HRO761 monotherapy included dose escalation, followed by randomized dose optimization as needed.
- 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
- • All patients (Arm A, B and C) will have available archival tumor tissue obtained prior to study treatment initiation, to allow retrospective MSIhi/dMMR status confirmation. A newly obtained biopsy will only be collected at screening if there is no archival tumor tissue available and if safe and medically feasible according to treating institution's guidelines. Exceptions may be considered after documented discussion with Novartis.
- CFDA:
- 11. Patients with advanced, unresectable, or metastatic MSIhi or MMR-deficient (dMMR) solid tumors who have progressed after prior standard therapy or are intolerant to prior standard therapy. Group A: Patients must have experienced disease progression after receiving all available standard therapies (including chemotherapy or targeted therapy, and/or prior immune checkpoint inhibitor therapy). Group B: Patients should have received standard therapy, i.e., chemotherapy and/or targeted therapy. Patients should have previously received checkpoint inhibitor therapy for advanced disease, or be expected to benefit from anti-PD1 checkpoint inhibitor therapy (as part of HRO761 combined with pembrolizumab). Group C: Patients must have experienced disease progression during their most recent treatment for advanced disease (including a prior immune checkpoint inhibitor therapy).2Eastern Cooperative Oncology Group (ECOG) Performance Status Score ≤ 13There are measurable lesions as determined by RECIST v1.1.4For the HRO761 sa group (Group A) only in the dose exploration portion: According to treatment facility guidelines, the patient's disease site must be suitable for biopsy, and the patient must be a candidate for tumor biopsy. The patient must be willing to undergo a new tumor biopsy at screening and during study treatment. If safe and medically feasible, biopsies of the same lesion are preferred. Exceptions may be considered after discussion with Novartis and on record.5All patients (Groups A, B, and C) will have access to archived tumor tissue prior to the start of study treatment (this will also be required for Group A patients who have newly obtained tumor biopsy samples at screening) to allow for retrospective confirmation of MSIhi/dMMR status.
- 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
- CFDA:
- 1Heart failure or clinically significant heart disease2Clinically significant ocular damage3Patients with primary central nervous system (CNS) tumors or tumors that have metastasized to the CNS4Human Immunodeficiency Virus (HIV) Infection5Active hepatitis B virus (HBV), hepatitis C virus (HCV), or tuberculosis infection. Patients whose disease is controlled under antiviral treatment are not excluded.6History of severe hypersensitivity to any component of the investigational drug7Gastrointestinal dysfunction or disease that may significantly alter the absorption of the study drug (e.g., severe ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection), or intestinal obstruction, except for gastrectomy.
Clinical Study Information for Healthcare Providers
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