Trial Title:
A Study on Tuvusertib (Oral ATR Inhibitor) in Combination With PLX038 (Topo1 Inhibitor) in Patients With Advanced Solid Tumors
NCT ID:
NCT06337630
Condition:
Solid Tumor
Conditions: Official terms:
Neoplasms
Conditions: Keywords:
Pretreated
Metastatic
Locally
Advanced triple negative breast
ATM Gene Mutation
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Phase I with a dose finding cohort, followed by expansion cohorts in pre-specified tumor
types.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
PLX038 + Tuvusertib
Description:
Dose escalation will be conducted on the grid defined by the 4 doses of PLX038 (800
mg/m², 1000 mg/m², 1300 mg/m² and 1700 mg/m² IV every 21 days D1=D22) and 3 doses of
Tuvusertib (90 mg, 130 mg and 180 mg QD for 10 days from D3, D3-12). Premedication with
anti-emetic agents is not required prior to the initial infusion, but may be used for an
individual patient, as needed.
All included patients will receive PLX038 + Tuvusertib until progression of disease,
unacceptable toxicity, patient withdrawal of consent, investigator decision, lost to
follow-up, death, patient non-compliance, or study termination by Sponsor.
Arm group label:
Single arm: treatment with PLX038 and Tuvusertib
Summary:
Phase I with a dose finding cohort, followed by expansion cohorts in pre-specified tumor
types.
Detailed description:
This is an open label, multi-centric phase I with, first, a dose escalation step using an
adaptation of the Bayesian Optimal INterval (BOIN) drug-combination, followed by 2 dose
expansion cohorts using the Simon 2-stage design.
Dose escalation step Dose escalation will be conducted on the grid defined by the 4 doses
of PLX038 (800 mg/m², 1000 mg/m², 1300 mg/m² and 1700 mg/m² IV every 21 days D1=D22) and
3 doses of Tuvusertib (90 mg, 130 mg and 180 mg QD for 10 days from D3, D3-12).
Premedication with anti-emetic agents is not required prior to the initial infusion, but
may be used for an individual patient, as needed.
starting combination level is c1 (PLX038 800mg/m2 and Tuvusertib 90mg). Groups of 3
patients will be sequentially enrolled. One week between the enrollment of the 1st
patient and the 2 following patients is mandatory at a new combination level. The
decision to (de)-escalate one of the two agents depends on the outcome of all patients
treated at the current combination.
Expansion cohorts Two expansion cohorts are planned, investigating the efficacy and
safety in pre-specified populations of interest.
Patients will be treated at the RP2D; 25 evaluable patients are needed in each cohort, to
account for possible non evaluable patients, up to 28 patients will be enrolled in each
cohort.
Patients enrolled in the phase I part at the RP2D and fulfilling the eligibility criteria
of one of the expansion cohorts will be counted in those 25 evaluable patients.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Willing and able to comply with the protocol and provide written informed consent
prior to study-specific screening procedures.
- Age ≥ 18 years.
- Locally advanced or metastatic solid cancer that is not amenable to curative
treatment.
- Measurable disease (per RECIST version 1.1).
- Received a minimum of one and a maximum of six prior cytotoxic chemotherapy regimens
for locally advanced or metastatic cancer.
- Resolution of chemotherapy and radiation therapy related toxicities to NCI-CTCAE
version 5.0 Grade 1 or lower severity, except for stable sensory neuropathy (≤ Grade
2), alopecia (any grade), presence of clinically managed chronic autoimmune AEs from
prior immune therapy.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Adequate organ function (obtained within 14 days prior to treatment start) as
evidenced by:
i. Absolute neutrophil count (ANC) ≥ 1.5 X 109/L; ii. Hemoglobin (Hgb) ≥ 9 g/dL;
iii. Platelet count ≥ 100 X 109/L; iv. Bilirubin ≤ 1.5 X upper limit of normal
(ULN), except for patients with a documented history of Gilbert's disease (≤ 2 X
ULN); v. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 2.5
X ULN (for patients with liver metastases ≤ 5 X ULN); vi. Alkaline phosphatase (ALP)
≤ 3 X ULN (for patients with liver metastases, ≤ 5 X ULN); vii. Serum creatinine ≤
1.5 mg/dL (133 μmol/L) or calculated creatinine clearance ≥ 50 mL/min (using
Cockcroft-Gault formula); viii. Women of childbearing potential (WCBP): negative
serum pregnancy test.
- Full blood count parameters described above must meet the thresholds with no
transfusion or growth factor support in the past 14 days.
- Patients covered by social security or health insurance in compliance with the
national legislation relating to biomedical research.
- The willingness to remain on contraception of childbearing potential for the
duration of study treatment plus 7 months (women) or 4 months (men).
Exclusion Criteria:
- Patients who have had a last dose of IV chemotherapy within 21 days, last dose of
oral cytotoxic chemotherapy, radiotherapy, biological therapy, or investigational
therapy within 14 days prior to treatment start.
- Patients who have had any major surgery within 28 days prior to inclusion.
- Patients with chronic inflammatory bowel disease and/or bowel obstruction.
- Concomitant use of other agents for the treatment of cancer (except for LHRH
agonist/antagonist) or any investigational agent(s).
- Brain metastases, unless local therapy was completed and use of corticosteroids for
this indication discontinued for at least 3 weeks prior to inclusion. Signs or
symptoms of brain metastases must be stable for at least 28 days prior to inclusion.
No known progression of brain metastases (by imaging as assessed by RECIST version
1.1) can have occurred. Patients with leptomeningeal disease or meningeal
carcinomatosis are excluded.
- Women who are either pregnant, lactating, planning to get pregnant.
- Patients receiving pharmacotherapy for hepatitis B or C, tuberculosis, or HIV.
- Patients with known liver disease diagnosed with Child-Pugh A or higher cirrhosis.
- Other current or previous stage III or IV malignancy diagnosed within 5 years of
study entry.
- Severe/uncontrolled intercurrent illness within the previous 28 days prior to
inclusion.
- Uncontrolled or poorly controlled arterial hypertension, symptomatic congestive
heart failure (New York Heart Association Classification ≥ Class III), uncontrolled
cardiac arrhythmia, calculated QTc average using the QTcF > 480 msec; unstable
angina pectoris, myocardial infarction or a coronary revascularization procedure,
cerebral vascular accident, transient ischemic attack, or any other significant
vascular disease within 180 days of study intervention start.
- Patients with ongoing active infection (requiring systemic treatment) and treatment
with live or live attenuated vaccine within 30 days of dosing.
- Any other significant medical, psychological, social or geographic conditions that
in the opinion of the Investigator would impair study participation or cooperation.
- Patients deprived of their liberty or under guardianship.
Dose expansion additional inclusion criteria
Breast cancer
- Triple-negative breast cancer (both ER and PR <10%, HER2-negative or HER2-low,
locally assessed).
- Prior therapy (administered in the neoadjuvant, adjuvant and/or metastatic setting)
with an anthracycline, taxane and sacituzumab govitecan (unless not medically
appropriate or contraindicated for the patient).
- Patients with known gBRCA mutations must have received a PARP inhibitor in the
metastatic setting.
- Patients whose cancer has a CPS score ≥10 must have received prior pembrolizumab
unless (i) contra-indicated (ii) CPS score or pembrolizumab not available at time of
first line treatment start.
ATM-mutated solid cancers
● Inactivating mutation of ATM (presence of truncating mutation or R337/R3008 missense
mutation of ATM mono and/or biallelic, assessed by next-generation sequencing in a
certified French genomics platform).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Institut Curie
Address:
City:
Paris
Zip:
75005
Country:
France
Contact:
Last name:
François-Clément BIDARD
Email:
francois-clement.bidard@curie.fr
Investigator:
Last name:
François-Clément BIDARD
Email:
Principal Investigator
Facility:
Name:
Institut Curie
Address:
City:
Saint-Cloud
Zip:
92210
Country:
France
Contact:
Last name:
François-Clément BIDARD
Email:
francois-clement.bidard@curie.fr
Investigator:
Last name:
François-Clément BIDARD
Email:
Principal Investigator
Start date:
June 15, 2024
Completion date:
February 15, 2029
Lead sponsor:
Agency:
Institut Curie
Agency class:
Other
Collaborator:
Agency:
ProLynx LLC
Agency class:
Industry
Collaborator:
Agency:
Merck Sharp & Dohme LLC
Agency class:
Industry
Source:
Institut Curie
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06337630
