Clinical trial NCT05838768: 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
Overall status: RECRUITING
Phase: PHASE1
Conditions: 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
pembrolizumab
irinotecan
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2023-05-03
Enrollment: 327
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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 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.

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 pembrolizumab or irinotecan.

Pembrolizumab and irinotecan are drugs approved in several countries and 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 HRO761 with pembrolizumab or irinotecan also will 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 pembrolizumab 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.

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 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
* 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

Primary outcomes:
measure: Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: at month 36
measure: Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only)
timeFrame: at Day 28
measure: Frequency of dose interuptions as a measure of tolerability
timeFrame: at month 36
measure: Frequency of dose discontinuations as a measure of tolerability
timeFrame: at month 36
measure: Frequency of dose reductions as a measure of tolerability
timeFrame: at month 36
Secondary outcomes:
measure: Overall Response Rate (ORR) per RECIST v1.1
timeFrame: at month 36
measure: Disease Control Rate (DCR) per RECIST v1.1
timeFrame: at month 36
measure: Progression Free Survival (PFS) per RECIST v1.1
timeFrame: at month 36
measure: Duration of Response (DOR) per RECIST v1.1
timeFrame: at month 36
measure: Plasma concentrations of HRO761
timeFrame: at Day 1, Day 8, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, Day 309 and EOT
measure: PK parameter (Tmax) of HRO761
timeFrame: at month 12
measure: PK parameter (Cmax) of HRO761
timeFrame: at month 12
measure: PK parameter (AUC) of HRO761
timeFrame: at month 12
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California LA
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: New York
country: United States
facility: Columbia University Medical Ctr
state: New York
city: Houston
country: United States
facility: Univ of TX MD Anderson Cancer Cntr
state: Texas
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
References: