search
Back to results

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

Primary Purpose

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

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
HRO761
tislelizumab
irinotecan
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal Cancers focused on measuring Phase I/Ib, MSIhi (Microsatellite Instability-High), dMMR (Mismatch Repair Deficient), solid tumors, CRC (Colorectal cancer), advanced cancer, metastatic, HRO761, tislelizumab, irinotecan

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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. Other protocol-defined inclusion/exclusion criteria may apply

Sites / Locations

  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

A: HRO761 single agent

B: HRO761 + tislelizumab

C: HRO761 + irinotecan

Arm Description

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

phase Ib (Dose escalation and expansion)

phase Ib (Dose escalation and expansion)

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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.

Secondary Outcome Measures

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).
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)
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.
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.
Plasma concentrations of HRO761
Plasma concentrations of HRO761 will be measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.
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.
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.
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.
Serum concentrations of tislelizumab
Serum concentrations of tislelizumab will be measured using a validated immunoassay
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.
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.
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.
Number of participants with anti tislelizumab antibodies
Anti-tislelizumab antibodies determined from serum using validated Enzyme-Linked Immunosorbent Assay (ELISA).

Full Information

First Posted
April 5, 2023
Last Updated
July 27, 2023
Sponsor
Novartis Pharmaceuticals
search

1. Study Identification

Unique Protocol Identification Number
NCT05838768
Brief Title
Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair Deficiency.
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.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 27, 2023 (Actual)
Primary Completion Date
August 11, 2026 (Anticipated)
Study Completion Date
August 11, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal Cancers
Keywords
Phase I/Ib, MSIhi (Microsatellite Instability-High), dMMR (Mismatch Repair Deficient), solid tumors, CRC (Colorectal cancer), advanced cancer, metastatic, HRO761, tislelizumab, irinotecan

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study 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.
Allocation
Non-Randomized
Enrollment
327 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
A: HRO761 single agent
Arm Type
Experimental
Arm Description
phase Ib (Dose finding (Escalation and Optimization) and expansion)
Arm Title
B: HRO761 + tislelizumab
Arm Type
Experimental
Arm Description
phase Ib (Dose escalation and expansion)
Arm Title
C: HRO761 + irinotecan
Arm Type
Experimental
Arm Description
phase Ib (Dose escalation and expansion)
Intervention Type
Drug
Intervention Name(s)
HRO761
Intervention Description
Tablet
Intervention Type
Biological
Intervention Name(s)
tislelizumab
Other Intervention Name(s)
VDT482
Intervention Description
Concentrate for solution for infusion
Intervention Type
Drug
Intervention Name(s)
irinotecan
Intervention Description
Concentrate for solution for infusion
Primary Outcome Measure Information:
Title
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
at month 36
Title
Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only)
Description
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.
Time Frame
at Day 28
Title
Frequency of dose interuptions as a measure of tolerability
Description
Month 36 is assumed to be study end Number of dose interruptions by treatment group/arm as a measure of tolerability.
Time Frame
at month 36
Title
Frequency of dose discontinuations as a measure of tolerability
Description
Month 36 is assumed to be study end Number of dose discontinuations by treatment group/arm as a measure of tolerability.
Time Frame
at month 36
Title
Frequency of dose reductions as a measure of tolerability
Description
Month 36 is assumed to be study end Number of dose reductions by treatment group/arm as a measure of tolerability.
Time Frame
at month 36
Secondary Outcome Measure Information:
Title
Overall Response Rate (ORR) per RECIST v1.1
Description
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).
Time Frame
at month 36
Title
Disease Control Rate (DCR) per RECIST v1.1
Description
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)
Time Frame
at month 36
Title
Progression Free Survival (PFS) per RECIST v1.1
Description
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.
Time Frame
at month 36
Title
Duration of Response (DOR) per RECIST v1.1
Description
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.
Time Frame
at month 36
Title
Plasma concentrations of HRO761
Description
Plasma concentrations of HRO761 will be measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.
Time Frame
at Day 1, Day 8, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, Day 309 and EOT
Title
PK parameter (Tmax) of HRO761
Description
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.
Time Frame
at month 12
Title
PK parameter (Cmax) of HRO761
Description
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.
Time Frame
at month 12
Title
PK parameter (AUC) of HRO761
Description
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.
Time Frame
at month 12
Title
Serum concentrations of tislelizumab
Description
Serum concentrations of tislelizumab will be measured using a validated immunoassay
Time Frame
at Day 1, Day 8, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, Day 309 and EOT
Title
PK parameter (Tmax) of tislelizumab
Description
Cycle 12 (the duration of 1 cycle is 28 days). Tmax determined by non-compartmental PK analysis of serum concentration-time profiles tislelizumab.
Time Frame
at month 12
Title
PK parameter (Cmax) of tislelizumab
Description
Cycle 12 (the duration of 1 cycle is 28 days). Cmax determined by non-compartmental PK analysis of serum concentration-time profiles tislelizumab.
Time Frame
at month 12
Title
PK parameter (AUC) of tislelizumab
Description
Cycle 12 (the duration of 1 cycle is 28 days). AUC determined by non-compartmental PK analysis of plasma concentration-time profiles tislelizumab.
Time Frame
at month 12
Title
Number of participants with anti tislelizumab antibodies
Description
Anti-tislelizumab antibodies determined from serum using validated Enzyme-Linked Immunosorbent Assay (ELISA).
Time Frame
Up to 36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
1-888-669-6682
Email
novartis.email@novartis.com
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
+41613241111
Facility Information:
Facility Name
Novartis Investigative Site
City
Kashiwa
State/Province
Chiba
ZIP/Postal Code
277 8577
Country
Japan
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Singapore
ZIP/Postal Code
119228
Country
Singapore
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

We'll reach out to this number within 24 hrs