An Open-Label Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of M4344 (formerly VX-803) as a Single Agent and in Combination With Cytotoxic Chemotherapy in Participants With Advanced Solid Tumors

Completed

• Conditions: advanced solid tumors; Solid tumors; 10025319

• Registration Number: NL-OMON50338
• Lead Sponsor: Merck

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 23 April 2024

Recruitment & Eligibility

• Status: Completed
• Sex: Not specified
• Target Recruitment: 16

Inclusion Criteria

Subjects who meet all of the following inclusion criteria will be eligible for
this study:
1. Male and female subjects *18 years of age
2. Disease status:
Part A2 and A3: Subjects with histologically or cytologically confirmed
malignant advanced solid
tumors for which no standard therapy is available which may convey
clinical benefit.
Part B: Subjects with 1 histologically or cytologically confirmed
malignant advanced solid tumors for which no standard therapy is
available which may convey clinical benefit, and/or subjects must have
progressed after at least 1 prior chemotherapy regimen in the metastatic
setting, and for which carboplatin would be considered standard of care.
Part C1, C2, and C3: Participants with 1 histologically or cytologically
confirmed malignant advanced solid tumors for which no recommended standard
therapy is available (i.e. participants who have exhausted all standard of care
options according to NCCN Guidance) which may convey clinical benefit, and
whose tumor has at least 1 of the following biomarkers as determined by a
central trial assay or by an assay with appropriate regulatory status:
- C1 or C4: loss-of-function mutations in the gene ARID1A
- C2 or C5: loss-of-function mutations in the genes ATRX and/or DAXX
- C3 or C6: loss-of-function mutations in the gene ATM
3. Measurable disease according to RECIST criteria (Version 1.1)
4. WHO performance status of 0 or 1
5. Life expectancy of *12 weeks
6. Hematological and biochemical indices within the ranges shown below at
Screening.
These values must be confirmed at the first day of dosing, before study drug
administration:
a. Hemoglobin: *9.0 g/dL for Parts A and B; *8.0 g/dL and no blood transfusions
in
the preceding 28 days for Part C
b. Absolute neutrophil count: *2.0 x 109/L
c. Platelet count: *125 x 109/L.
d. Serum bilirubin: *1.5 x upper limit of normal (ULN), except in the case of
known
or suspected Gilbert*s syndrome.
e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and
alkaline
phosphatase (liver origin): *2.5 x ULN or *5 x ULN in presence of liver
metastases
f. Serum albimin *2.5g/dL
g. Estimated glomerular filtration rate: *50 mL/min for Parts A and B; *40
mL/min
for Parts C
h. Prothrombin time: <1.25 x ULN
i. In addition, there should not be other clinically significant metabolic or
hematologic abnormalities that are uncorrectable or that require ongoing,
recurrent pharmacologic management.
7. Sign and date an informed consent document
8. Willing and able to comply with scheduled visits, treatment plan, lifestyle,
laboratory
tests, contraceptive guidelines, and other study procedures

Exclusion Criteria

Subjects who meet any of the following exclusion criteria are not eligible for
this study:
1. Radiotherapy, unless brief course for palliative therapy, endocrine therapy,
immunotherapy, or chemotherapy during the 4 weeks (6 weeks for nitrosoureas and
Mitomycin-C, and 4 weeks for investigational medicinal products) or 4 drug
half-lives
before first dose of study drug, whichever is greater
2. Part B1: More than 6 cycles of prior therapy with carboplatin, unless
discussed with and
approved by the Merck medical monitor.
3. Ongoing toxic manifestations of previous treatments. Exceptions to this are
alopecia or
certain Grade 1 toxicities, which in the opinion of the investigator should not
exclude the
subject.
Part B1. Any known history of Grade 4 thrombocytopenia with any prior
chemotherapy regimen (not applicable for Parts C)
4. Brain metastases unless asymptomatic, treated, stable, and not
requiring steroids for at least 4 weeks before first dose of study drug
5. Female subjects who are already pregnant or lactating, or plan to become
pregnant within
6 months of the last dose of study drug are excluded. Female subjects of
childbearing
potential must adhere to contraception guidelines as outlined in Section
11.7.5.1. Female
subjects will be considered to be of nonchildbearing potential if they have
undergone
surgical hysterectomy or bilateral oophorectomy or have been amenorrheic for
over
2 years with a screening serum follicle-stimulating hormone (FSH) level within
the
laboratory*s reference range for postmenopausal females.
6. Male subjects with partners of childbearing potential must agree to adhere to
contraception guidelines in Section 11.7.5.1. Men with pregnant or lactating
partners or
partners who plan to become pregnant during the study or within 6 months of the
last
dose of study drug are excluded.
7. Major surgery *4 weeks before first dose of study drug or incomplete
recovery from a
prior major surgical procedure
8. Cardiac conditions as follows:
a. Clinically significant cardiovascular event within 6 months before study
entry:
i. congestive heart failure requiring therapy
ii. unstable angina pectoris
iii. myocardial infarction
iv. Class II/III/IV cardiac disease (New York Heart Association)
v. presence of severe valvular heart disease
vi. presence of a ventricular arrhythmia requiring treatment
b. History of arrhythmia that is symptomatic or requires treatment
(CTCAE Grade 2), symptomatic or uncontrolled atrial fibrillation despite
treatment, or asymptomatic sustained ventricular tachycardia. Subjects with
atrial fibrillation controlled by medication are permitted.
c. Uncontrolled hypertension (blood pressure *160/100 despite optimal therapy)
d. Second or third degree heart block with or without symptoms
e. QTc >470 msec (by either Fridericia*s or Bazett*s correction) not due to
electrolyte abnormality and that does not resolve with correction of
electrolytes
f. History of congenital long QT syndrome
g. History of torsades de pointes (or any concurrent medication with a known
risk of inducing torsades de pointes)
h. Clinically-significant abnormality, including ejection fraction below normal
institutional limits, present on transthoracic echocardiogram performed at
Screening, for Parts A and B
9. Prior bone marrow tran

Study & Design

• Study Type: Interventional
• Study Design: Not specified