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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05838768

Collaborator

(none)

327

Enrollment

Location

Arms

Anticipated Duration (Months)

8.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal Cancers	Drug: HRO761 Biological: tislelizumab Drug: irinotecan	Phase 1

Detailed 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 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

327 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Masking Description:

This is an open label study. Treatment will be open to patients, Investigator staff, persons performing the assessments and the Sponsor clinical trial team. For the dose escalation and dose expansion, no randomization will be performed. For the dose optimization (HRO761 single agent arm only), patients will be equally randomized to the two selected HRO761 single agent treatment dose levels.

Primary Purpose:

Treatment

Official Title:

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.

Anticipated Study Start Date :

May 12, 2023

Anticipated Primary Completion Date :

Aug 11, 2026

Anticipated Study Completion Date :

Aug 11, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A: HRO761 single agent phase Ib (Dose finding (Escalation and Optimization) and expansion)	Drug: HRO761 Tablet
Experimental: B: HRO761 + tislelizumab phase Ib (Dose escalation and expansion)	Drug: HRO761 Tablet Biological: tislelizumab Concentrate for solution for infusion Other Names: VDT482
Experimental: C: HRO761 + irinotecan phase Ib (Dose escalation and expansion)	Drug: HRO761 Tablet Drug: irinotecan Concentrate for solution for infusion

Arm

Intervention/Treatment

Experimental: A: HRO761 single agent

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

Drug: HRO761

Tablet

Experimental: B: HRO761 + tislelizumab

phase Ib (Dose escalation and expansion)

Drug: HRO761

Tablet

Biological: tislelizumab

Concentrate for solution for infusion

Other Names:

VDT482

Experimental: C: HRO761 + irinotecan

phase Ib (Dose escalation and expansion)

Drug: HRO761

Tablet

Drug: irinotecan

Concentrate for solution for infusion

Outcome Measures

Primary Outcome Measures

Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) [at month 36]
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.
Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only) [at Day 28]
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.
Frequency of dose interuptions as a measure of tolerability [at month 36]
Month 36 is assumed to be study end Number of dose interruptions by treatment group/arm as a measure of tolerability.
Frequency of dose discontinuations as a measure of tolerability [at month 36]
Month 36 is assumed to be study end Number of dose discontinuations by treatment group/arm as a measure of tolerability.
Frequency of dose reductions as a measure of tolerability [at month 36]
Month 36 is assumed to be study end Number of dose reductions by treatment group/arm as a measure of tolerability.

Secondary Outcome Measures

Overall Response Rate (ORR) per RECIST v1.1 [at month 36]
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).
Disease Control Rate (DCR) per RECIST v1.1 [at month 36]
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)
Progression Free Survival (PFS) per RECIST v1.1 [at month 36]
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.
Duration of Response (DOR) per RECIST v1.1 [at month 36]
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.
Plasma concentrations of HRO761 [at Day 1, Day 8, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, Day 309 and EOT]
Plasma concentrations of HRO761 will be measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.
PK parameter (Tmax) of HRO761 [at month 12]
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.
PK parameter (Cmax) of HRO761 [at month 12]
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.
PK parameter (AUC) of HRO761 [at month 12]
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.
Serum concentrations of tislelizumab [at Day 1, Day 8, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, Day 309 and EOT]
Serum concentrations of tislelizumab will be measured using a validated immunoassay
PK parameter (Tmax) of tislelizumab [at month 12]
Cycle 12 (the duration of 1 cycle is 28 days). Tmax determined by non-compartmental PK analysis of serum concentration-time profiles tislelizumab.
PK parameter (Cmax) of tislelizumab [at month 12]
Cycle 12 (the duration of 1 cycle is 28 days). Cmax determined by non-compartmental PK analysis of serum concentration-time profiles tislelizumab.
PK parameter (AUC) of tislelizumab [at month 12]
Cycle 12 (the duration of 1 cycle is 28 days). AUC determined by non-compartmental PK analysis of plasma concentration-time profiles tislelizumab.
Number of participants with anti tislelizumab antibodies [Up to 36 months]
Anti-tislelizumab antibodies determined from serum using validated Enzyme-Linked Immunosorbent Assay (ELISA).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.