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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05838768
Recruitment Status : Recruiting
First Posted : May 3, 2023
Last Update Posted : May 14, 2024
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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.
Actual Study Start Date : June 27, 2023
Estimated Primary Completion Date : January 30, 2030
Estimated Study Completion Date : January 31, 2030


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 Name: VDT482

Experimental: C: HRO761 + irinotecan
phase Ib (Dose escalation and expansion)
Drug: HRO761
Tablet

Drug: irinotecan
Concentrate for solution for infusion




Primary Outcome Measures :
  1. Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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.


  2. Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only) [ Time Frame: 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.

  3. Frequency of dose interuptions as a measure of tolerability [ Time Frame: at month 36 ]

    Month 36 is assumed to be study end

    Number of dose interruptions by treatment group/arm as a measure of tolerability.


  4. Frequency of dose discontinuations as a measure of tolerability [ Time Frame: at month 36 ]

    Month 36 is assumed to be study end

    Number of dose discontinuations by treatment group/arm as a measure of tolerability.


  5. Frequency of dose reductions as a measure of tolerability [ Time Frame: 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 :
  1. Overall Response Rate (ORR) per RECIST v1.1 [ Time Frame: 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).


  2. Disease Control Rate (DCR) per RECIST v1.1 [ Time Frame: 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)


  3. Progression Free Survival (PFS) per RECIST v1.1 [ Time Frame: 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.


  4. Duration of Response (DOR) per RECIST v1.1 [ Time Frame: 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.


  5. Plasma concentrations of HRO761 [ Time Frame: 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.

  6. PK parameter (Tmax) of HRO761 [ Time Frame: 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.


  7. PK parameter (Cmax) of HRO761 [ Time Frame: 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.


  8. PK parameter (AUC) of HRO761 [ Time Frame: 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.


  9. Serum concentrations of tislelizumab [ 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 ]
    Serum concentrations of tislelizumab will be measured using a validated immunoassay

  10. PK parameter (Tmax) of tislelizumab [ Time Frame: 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.


  11. PK parameter (Cmax) of tislelizumab [ Time Frame: 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.


  12. PK parameter (AUC) of tislelizumab [ Time Frame: 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.


  13. Number of participants with anti tislelizumab antibodies [ Time Frame: Up to 36 months ]
    Anti-tislelizumab antibodies determined from serum using validated Enzyme-Linked Immunosorbent Assay (ELISA).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05838768


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, California
University Of California LA Dept of Onc Recruiting
Los Angeles, California, United States, 90095
Contact: Lisa Zhou    310-582-4069    LisaZhou@mednet.ucla.edu   
Principal Investigator: Zev A Wainberg         
United States, New York
Memorial Sloan Kettering Dept. of MSKCC Recruiting
New York, New York, United States, 10017
Contact: Jill Weiss    +1 646 227 2157    weissj2@mskcc.org   
Principal Investigator: Michael Bonner Foote         
Columbia University Medical Ctr . Recruiting
New York, New York, United States, 10032
Contact: Joy Kim    646-317-4850    jk4704@cumc.columbia.edu   
Principal Investigator: Edmond Chan         
United States, Texas
Univ of TX MD Anderson Cancer Cntr Primary Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Timothy Yap         
Belgium
Novartis Investigative Site Recruiting
Bruxelles, Belgium, 1200
France
Novartis Investigative Site Recruiting
Bordeaux, France, 33076
Novartis Investigative Site Recruiting
Marseille, France, 13273
Germany
Novartis Investigative Site Recruiting
Essen, Germany, 45147
Novartis Investigative Site Recruiting
Ulm, Germany, 89081
Israel
Novartis Investigative Site Recruiting
Tel Aviv, Israel, 6423906
Italy
Novartis Investigative Site Recruiting
Rozzano, MI, Italy, 20089
Japan
Novartis Investigative Site Recruiting
Kashiwa, Chiba, Japan, 277 8577
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 03722
Norway
Novartis Investigative Site Recruiting
Oslo, Norway, NO-0379
Singapore
Novartis Investigative Site Recruiting
Singapore, Singapore, 119228
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Valencia, Comunidad Valenciana, Spain, 46010
Novartis Investigative Site Recruiting
Madrid, Spain, 28009
Taiwan
Novartis Investigative Site Recruiting
Taipei, Taiwan, 10002
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT05838768    
Other Study ID Numbers: CHRO761A12101
2022-502314-93-00 ( Registry Identifier: EU CTIS )
First Posted: May 3, 2023    Key Record Dates
Last Update Posted: May 14, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Phase I/Ib
MSIhi (Microsatellite Instability-High)
dMMR (Mismatch Repair Deficient)
solid tumors
CRC (Colorectal cancer)
advanced cancer
metastatic
HRO761
tislelizumab
irinotecan
Additional relevant MeSH terms:
Layout table for MeSH terms
Genomic Instability
Colorectal Neoplasms
Microsatellite Instability
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Pathologic Processes
Irinotecan
Tislelizumab
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological