MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal CancersPhase 1NCT05838768
Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair Deficiency.
A Phase 1 study testing HRO761, pembrolizumab and irinotecan in people with MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal Cancers, run by Novartis Pharmaceuticals at 28 sites in 15 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal Cancers
- What is being tested?
- HRO761, pembrolizumab and irinotecan
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 123 participants
- Where
- 28 sitesin 15 countries
- Study dates
- 27 Jun 2023to 31 Aug 2027
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
28 sites in 15 countries.
28 sites in 15 countries
United States6 sites
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Univ of TX MD Anderson Cancer Cntr
Houston, Texas, 77030
University of California LA
Los Angeles, California, 90095
Memorial Sloan Kettering
New York, New York, 10017
Columbia University Medical Ctr
New York, New York, 10032
UCSF
San Francisco, California, 94115
Spain4 sites
Novartis Investigative Site
Barcelona, 08035
Novartis Investigative Site
Madrid, 28009
Novartis Investigative Site
Madrid, 28040
Novartis Investigative Site
Valencia, 46010
France3 sites
Novartis Investigative Site
Bordeaux, 33076
Novartis Investigative Site
Marseille, 13273
Novartis Investigative Site
Toulouse, 31059
China2 sites
Novartis Investigative Site
Beijing, 100036
Novartis Investigative Site
Guangzhou, 510655
Italy2 sites
Novartis Investigative Site
Milan, MI, 20162
Novartis Investigative Site
Rozzano, MI, 20089
United Kingdom2 sites
Novartis Investigative Site
London, SW3 6JJ
Novartis Investigative Site
Oxford, Oxford, OX3 7LE
About this study
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.
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.
Read the 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.
- Conditions
- MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal Cancers
- Being tested
- HRO761, pembrolizumab, irinotecan
- Keywords
- Phase I/Ib, MSIhi (Microsatellite Instability-High), dMMR (Mismatch Repair Deficient), solid tumors, CRC (Colorectal cancer), advanced cancer, metastatic, HRO761, pembrolizumab, irinotecan
- Medical subject headings
- Turcot syndrome, Colorectal Neoplasms, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HRO761Drug
Tablet
pembrolizumabBiological
Concentrate for solution for infusion
irinotecanDrug
Concentrate for solution for infusion
| Study group | Role | What they receive |
|---|---|---|
| A: HRO761 single agent | Experimental | phase Ib (Dose finding (Escalation and Optimization) and expansion) Receives: Drug: HRO761 |
| B: HRO761 + pembrolizumab | Experimental | phase Ib (Dose escalation and expansion) Receives: Drug: HRO761; Biological: pembrolizumab |
| C: HRO761 + irinotecan | Experimental | phase Ib (Dose escalation and expansion) Receives: Drug: HRO761; Drug: irinotecan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: at month 36
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.
Measured: at Day 28
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.
Measured: at month 36
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.
Measured: at month 36
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.
Measured: at month 36
Secondary outcomes (8)
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).
Measured: at month 36
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)
Measured: at month 36
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.
Measured: at month 36
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.
Measured: at month 36
Plasma concentrations of HRO761
Plasma concentrations of HRO761 will be measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.
Measured: at Day 1, Day 8, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, and Day 309
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.
Measured: at month 12
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.
Measured: at month 12
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.
Measured: at month 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 May 2023
- Study start27 Jun 2023
- Primary completion31 Aug 2027 (estimated)
- Study completion31 Aug 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal CancersStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 123 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05838768
- Sponsor's protocol ID
- CHRO761A12101
- Other IDs
- 2022-502314-93-00
- Status last verified
- Oct 2026
- First submitted
- 5 Apr 2023
- Last updated
- 21 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No