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

Study Overview
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Brief Summary
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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 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.

Detailed Description
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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 tislelizumab or irinotecan. Tislelizumab has been used in other cancer studies in the past few years and irinotecan is a drug approved in several countries and is 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 HRO761with tislelizumab or irinotecan will also first 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 tislelizumab 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.

Official Title
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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.

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

Intervention / Treatment
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* Drug: HRO761
* Biological: tislelizumab
* Drug: irinotecan


Participation Criteria
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Eligibility Criteria
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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 may have received prior chemotherapy or targeted therapy but should not have or without prior treatment with immune checkpoint inhibitors. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: HRO761 single agent<br>phase Ib (Dose finding (Escalation and Optimization) and expansion) | Drug: HRO761<br>* Tablet<br>|
| Experimental: B: HRO761 + tislelizumab<br>phase Ib (Dose escalation and expansion) | Drug: HRO761<br>* Tablet<br>Biological: tislelizumab<br>* Concentrate for solution for infusion<br>* Other names: VDT482;|
| Experimental: C: HRO761 + irinotecan<br>phase Ib (Dose escalation and expansion) | Drug: HRO761<br>* Tablet<br>Drug: irinotecan<br>* Concentrate for solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Month 36 is assumed to be study end. Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs) and laboratory results qualifying and reported as AEs. | at month 36 | 
| Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only) | A DLT is defined as an adverse event or abnormal laboratory value that is not primarily related to disease, disease progression, intercurrent illness/injury, or concomitant medications that occurs within the first 28 days of study treatment and meets a defined criteria. | at Day 28 | 
| Frequency of dose interuptions as a measure of tolerability | Month 36 is assumed to be study end Number of dose interruptions by treatment group/arm as a measure of tolerability. | at month 36 | 
| Frequency of dose discontinuations as a measure of tolerability | Month 36 is assumed to be study end Number of dose discontinuations by treatment group/arm as a measure of tolerability. | at month 36 | 
| Frequency of dose reductions as a measure of tolerability | Month 36 is assumed to be study end Number of dose reductions by treatment group/arm as a measure of tolerability. | at month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) per RECIST v1.1 | Month 36 is assumed to be study end ORR is the percentage of patients with a best overall response of Complete Response (CR) or Partial Response (PR). | at month 36 | 
| Disease Control Rate (DCR) per RECIST v1.1 | Month 36 is assumed to be study end DCR is the percentage of patients with a best overall response of CR or PR or Stable Disease (SD) | at month 36 | 
| Progression Free Survival (PFS) per RECIST v1.1 | Month 36 is assumed to be study end PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. | at month 36 | 
| Duration of Response (DOR) per RECIST v1.1 | Month 36 is assumed to be study end DOR is the time between the date of first documented response (CR or PR) and the date of progression or death due to any cause. | at month 36 | 
| Plasma concentrations of HRO761 | Plasma concentrations of HRO761 will be measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. | at Day 1, Day 8, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, Day 309 and EOT | 
| PK parameter (Tmax) of HRO761 | Cycle 12 (the duration of 1 cycle is 28 days). Time to maximum observed concentration (Tmax) determined by non-compartmental PK analysis of plasma concentration-time profiles HRO761. | at month 12 | 
| PK parameter (Cmax) of HRO761 | Cycle 12 (the duration of 1 cycle is 28 days). Maximum observed concentration (Cmax) determined by non-compartmental pharmacokinetic (PK) analysis of plasma concentration-time profiles HRO761. | at month 12 | 
| PK parameter (AUC) of HRO761 | Cycle 12 (the duration of 1 cycle is 28 days). Area under the plasma concentration-time curve (AUC) determined by non-compartmental PK analysis of plasma concentration-time profiles HRO761. | at month 12 | 
| Serum concentrations of tislelizumab | Serum concentrations of tislelizumab will be measured using a validated immunoassay | at Day 1, Day 8, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, Day 309 and EOT | 
| PK parameter (Tmax) of tislelizumab | Cycle 12 (the duration of 1 cycle is 28 days). Tmax determined by non-compartmental PK analysis of serum concentration-time profiles tislelizumab. | at month 12 | 
| PK parameter (Cmax) of tislelizumab | Cycle 12 (the duration of 1 cycle is 28 days). Cmax determined by non-compartmental PK analysis of serum concentration-time profiles tislelizumab. | at month 12 | 
| PK parameter (AUC) of tislelizumab | Cycle 12 (the duration of 1 cycle is 28 days). AUC determined by non-compartmental PK analysis of plasma concentration-time profiles tislelizumab. | at month 12 | 
| Number of participants with anti tislelizumab antibodies | Anti-tislelizumab antibodies determined from serum using validated Enzyme-Linked Immunosorbent Assay (ELISA). | Up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I/Ib, MSIhi (Microsatellite Instability-High), dMMR (Mismatch Repair Deficient), solid tumors, CRC (Colorectal cancer), advanced cancer, metastatic, HRO761, tislelizumab, irinotecan