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

NCT05838768
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Phase
Phase 1
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Recruitment status
Active, not recruiting
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Participants
123
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Lead sponsor
Novartis Pharmaceuticals
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Start date
2023-06-27
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Number of sites
28
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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 pembrolizumab 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.
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Short title
Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair Deficiency.
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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.
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Control arm
Open label
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Registry reports results
No
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Listing at source
Listed
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Recruitment status
Active, not recruiting
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Phase
Phase 1
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Study type
Interventional
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Completion date
2027-08-31
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First posted
2023-05-03
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Registry last updated
2026-10-21
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Primary completion date
2027-08-31
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Start date
2023-06-27
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Actual participants
123
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Participants
123
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Participant count basis
Actual
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Protocol amendments
4
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Number of sites
28
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Data monitoring committee
Yes
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Registry sponsor category
Industry
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Lead sponsor
Novartis Pharmaceuticals
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Source registry
ClinicalTrials.gov
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Registry ID
NCT05838768
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ClinicalTrials.gov ID
NCT05838768
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Registry record
Open registry record
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Allocation
Not randomised
Model
Sequential
Purpose
Treatment
Masking
No masking
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.
Sources for study design
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  1. Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Timeframe: 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)

    Timeframe: 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

    Timeframe: 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

    Timeframe: 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

    Timeframe: at month 36

    Month 36 is assumed to be study end Number of dose reductions by treatment group/arm as a measure of tolerability.

  1. Overall Response Rate (ORR) per RECIST v1.1

    Timeframe: 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

    Timeframe: 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

    Timeframe: 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

    Timeframe: 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

    Timeframe: at Day 1, Day 8, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, and Day 309

    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

    Timeframe: 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

    Timeframe: 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

    Timeframe: 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.

Sources for outcomes
clinicaltrials.gov

Sex
All
Age groups
Adults, Older adults
Minimum age
18 Years
Maximum age
100 Years
Healthy volunteers
No

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 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.

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

Sources for eligibility
clinicaltrials.gov

  • University of California LALos Angeles, United States
  • UCSFSan Francisco, United States
  • Dana Farber Cancer InstituteBoston, United States
  • Memorial Sloan KetteringNew York, United States
  • Columbia University Medical CtrNew York, United States
  • Univ of TX MD Anderson Cancer CntrHouston, United States
  • Novartis Investigative SiteBrussels, Belgium
  • Novartis Investigative SiteBeijing, China
  • Novartis Investigative SiteGuangzhou, China
  • Novartis Investigative SiteBordeaux, France
  • Novartis Investigative SiteMarseille, France
  • Novartis Investigative SiteToulouse, France
  • Novartis Investigative SiteEssen, Germany
  • Novartis Investigative SiteTel Aviv, Israel
  • Novartis Investigative SiteMilan, Italy
  • Novartis Investigative SiteRozzano, Italy
  • Novartis Investigative SiteKashiwa, Japan
  • Novartis Investigative SiteOslo, Norway
  • Novartis Investigative SiteSingapore, Singapore
  • Novartis Investigative SiteSeoul, South Korea
  • Novartis Investigative SiteBarcelona, Spain
  • Novartis Investigative SiteMadrid, Spain
  • Novartis Investigative SiteMadrid, Spain
  • Novartis Investigative SiteValencia, Spain
  • Novartis Investigative SiteStockholm, Sweden

And 3 more, listed on the interactive page.

Sources for sites
clinicaltrials.gov

Other registry identifiers

  • 2022-502314-93-00
Sources for references
clinicaltrials.gov

Related records

Drugs (3)

Lead sponsors (1)

Conditions (3)

Targets (3)