Primary Objective part A:* To evaluate the safety and tolerability of multiple ascending doses of single-agent M4344 administered BIW in subjects withadvanced solid tumors* To determine the MTD and/or RP2D of single-agent M4344 administered BIW in…
ID
Source
Brief title
Condition
- Other condition
- Lymphomas Hodgkin's disease
Synonym
Health condition
advanced solid tumors
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PART A:
- Safety parameters, including adverse events (AEs), clinical laboratory values
(serum chemistry and hematology), vital signs, and
electrocardiogram (ECG) assessments
- MTD and/or RP2D of single-agent M4344 administered BIW
PART A2:
- Safety parameters, including adverse events (AEs), clinical laboratory values
(serum chemistry and hematology), vital signs, and
electrocardiogram (ECG) assessments
- MTD and/or RP2D of single-agent M4344 administered with a twice daily or once
daily dose schedule
PART A3:
- Safety parameters, including AEs, clinical laboratory values (serum chemistry
and hematology), vital signs, and ECG assessments
- MTD and/or RP2D of single agent M4344 administered with a drug holiday
schedule.
PART B1:
- Safety parameters, including adverse events (AEs), clinical laboratory values
(serum chemistry and hematology), vital signs, and
electrocardiogram (ECG) assessments
- MTD and/or RP2D of M4344 administered in combination with carboplatin
PARTS C:
1) Occurrence of:
o Treatment-emergent adverse event (TEAEs) and treatment-related AEs graded
according to National Cancer Institute Common Terminology
Criteria for Adverse Events Laboratory abnormalities
o Clinically significant abnormal vital sign
o Clinically significant abnormal ECG
2) Objective response (i.e. confirmed complete response [CR] or partial
response [PR]) according to Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1
assessed by the Investigator
Secondary outcome
Part A:
- PK parameter estimates of single-agent M4344 administered BIW, derived from
plasma concentration-time data
- Objective tumor response (OR) and disease stabilization (SD) as evaluated by
Response Criteria Evaluation (Response Evaluation Criteria in Solid Tumors
[RECIST] 1.1
Part A2:
- PK parameteer estimates of single-agent M4344 administered with a twice daily
or once daily dose schedule, derived from plasma concentration-time data
- OR and disease stabilization as evaluated by RECIST 1.1
Part A3:
- PK parameter estimates of single agent M4344 (and metabolites as appropriate)
administered with a drug holiday dose schedule, derived from plasma
concentration time data
- OR and disease stabilization as evaluated by RECIST 1.1
Part B1:
- PK parameter estimates of M4344 administered in combination with carboplatin
derived from plasma concentration-time data
- OR as evaluated by Response Criteria Evaluation RECIST 1.1
Parts C:
- OR as evaluated by RECIST 1.1
- PFS
- OS
- DOR
- PK parameter estimates of M4344 (and metabolites as appropriate) in
individual participants with loss-of-function mutations)
- Time matched PK concentrations and digital ECG measures
Background summary
Merck KGaA is currently developing M4344, a potent and selective inhibitor of
ATR (inhibition constant [Ki]<150 pM) with a concentration resulting in 50%
maximal inhibition (IC50) of 8 nM for the treatment of advanced malignancies.
M4344 sensitizes many human cancer cell lines to the cytotoxic effects of
various DNA-damaging agents. In contrast, extensive studies with other ATR
inhibitors have shown that noncancer cells tolerate ATR inhibition with only a
reversible increase in growth arrest attributable to activation of
compensatory, ATM-mediated, DNA repair signaling8.
M4344 has shown efficacy and was well tolerated in mouse xenograft models both
as a single agent and in combination with DNA-damaging agents. In mouse
xenograft models derived from human cancer cell lines and patient-derived
explants, orally administered M4344 markedly
enhanced the antitumor activity of the DNA-damaging agent cisplatin,
carboplatin, and gemcitabine. In a mouse xenograft model of triple negative
breast cancer, M4344 dosed once weekly potentiated the efficacy of carboplatin,
and dosing of this combination led to complete tumor growth inhibition in
contrast to dosing of either agent alone.
Mutations in specific Deoxy ribonucleic acid damage response related genes
(including ARID1A, ATRX/DAXX and ATM) have been shown to increase reliance on
ATR signaling for tumor cell survival and growth. Published data suggest that
loss-of-function mutations in specific tumor genes involved in the Deoxy
ribonucleic acid (DNA) damage repair process as candidates to predict
sensitivity to ATR inhibitors as monotherapy. Williamson and co-authors showed
in an ribonucleic acid interference screening in cell lines that ARID1A was the
top hit gene that was synthetically lethal with the ATR inhibitor VX-821, and
that there was a noticeable statistically significant difference in sensitivity
to M6620 (VX-970) between the ARID1A wild type and mutated xenografts. Flynn
and coauthors demonstrated in vitro and in vivo that tumor cells preserving
chromosome integrity throughout the alternative lengthening of telomere
process, a mechanism associated with loss-of-function mutations in either the
genes ATRX or DAXX which involves DNA homologous recombination, are sensitive
to ATR inhibition. Antitumor activity of M4344 as monotherapy has been shown in
preclinical xenograft harboring such mutations. The co-inactivation of the
protein kinase ataxia telangiectasia mutated (ATM) and Rad3-related (ATR)
functions results in synthetic lethality, which has been shown in a gastric
cancer xenograft model carrying a mutation in ATM with the ATR inhibitor
AZD6738. Together, these data support the rationale that patients with solid
tumors harboring loss-of-function mutations in ARID1A, ATRX or DAXX, and ATM
may benefit from treatment with M4344 monotherapy, independent of anatomic
tumor localization.
Study objective
Primary Objective part A:
* To evaluate the safety and tolerability of multiple ascending doses of
single-agent M4344 administered BIW in subjects with
advanced solid tumors
* To determine the MTD and/or RP2D of single-agent M4344 administered BIW in
subjects with advanced solid
tumors
Secondary Objectives part A:
* To evaluate PK of single-agent M4344 when administered BIW in subjects with
advanced solid tumors
* To assess potential antitumor activity of single-agent M4344 when
administered BIW in subjects with advanced solid tumors
Primary Objectives part A2:
* To evaluate the safety and tolerability of multiple asc. doses of
single-agent M4344 administered in once or twice daily dose
* To determine the MTD and/or RP2D of single-agent M4344 administered in once
or twice daily dose
Secondary Objectives part A2:
* To evaluate PK of single-agent M4344 when administered once or twice daily
* To assess potential antitumor activity of single-agent M4344 when
administered once or twice daily
Primary Objectives part A3:
* To evaluate the safety and tolerability of multiple asc. doses of single
agent M4344 when administered in a drug holiday dose schedule
* To determine the MTD and/or RP2D of single agent M4344 administered in a drug
holiday dose schedule
Secondary Objectives part A3:
* To evaluate PK of single agent M4344 when administered in a drug holiday
dose schedule
* To assess preliminary antitumor activity of single agent M4344 when
administered in a drug holiday dose schedule
Primary Objective part B1:
* To evaluate the safety and tolerability of M4344 when administered in
combination with carboplatin
* To determine the MTD and/or RP2D of M4344 administered in combination with
carboplatin
Secondary Objective part B1:
-To evaluate the PK profile of M4344 when admin. in combin. with carboplatin
-To evaluate potential antitumor activity after admin. M4344 in combin. with
carboplatin
Primary Objectives Parts C:
* To evaluate the safety, tolerability and efficacy in terms of confirmed OR of
M4344 administered at doses and schedules determined as RP2D in Parts A, A2 or
A3 in participants with solid tumor harboring loss-of-function mutations in the
genes ARIDA (Part C1, C4), ATRX and/or DAXX (Part C2, C5), or ATM (Part C3,
C6).
Secondary Objectives Parts C:
- To further evaluate efficacy in terms of confirmed best overall response,
duration of response, progression free survival and overall survival time
of M4344 when administered in participants with loss-of-function mutations in
the genes ARID1A (Part C1, C4), ATRX and/or DAXX (Part C2, C5), or ATM (Part
C3, C6).
- To evaluate the PK of M4344 (and metabolites as appropriate) in individual
participants with loss-of-function mutations.
Objective Sub-study:
This study will investigate the PDPd of M4344 using clinical biomarkers. Paired
tumor biopsies (optional, Parts A2, A3, B1, C) in a tumor biopsy substudy and
serial PBMC samples ( Parts A2, A3, C) will be collected to evaluate markers of
ataxia talangiectasia mutated and Rad3-related protein (ATR) activation and
inhibitation, as well as of deoxy ribonucleic acid (DNA) damage.
Study design
This is an open-label Phase I, first-in-human clinical study conducted in
multiple Parts (Parts A, A2, A3, B1, C1, C2, C3, C4, C5 and C6).
Intervention
Part A:
Subjects will be administered M4344 BIW (dosed twice-weekly) as a single agent
on Days 1, 4, 8, 11, 15, and 18 of a 21-day cycle.
Starting dose 10mg. The dose of M4344 may be increased by up to 100% in a
subsequent subject, depending on
toxicities and tolerabilities observed.
Part A2:
Participants in Part A2 will initially be administered M4344 as a single agent
BID on a daily regimen. The M4344 starting dose in Part A2 will be 100 mg
(single dose) administered BID (200 mg daily).
Part A3:
Participants in Part A3 will be administered M4344 as a single agent in a dose
holiday schedule (3 days of dosing followed by 4 days of pausing [3d+/4d-] or 5
days of dosing followed by 2 days of pausing [5d+/2d-] or 7 days of dosing
followed by 7 days of pausing [7d+/7d-]) or 14 days of dosing followed by 7
days of pausing [14d+/7d-]).
Part B1:
For each M4344 dose level tested, subjects will receive carboplatin on Day 1,
and M4344 on Days 2 and 9 of a 21-day cycle.
Study Parts C will be expansion cohorts to explore potential antitumor efficacy
and to confirm the safety and tolerability of single agent M4344 administered
at a dose and schedule that has been determined as RP2D in study Part A, A2 or
A3.
Study burden and risks
As this is a First in Human study, the risks of the IP for humans are still
unknown.
Based on studies done in animals, the study drug, may cause the following
adverse events
Changes in numbers of some blood cell types, including Red Blood Cells, White
Blood Cells, and platelets.
Nausea, vomiting, diarrhea, or inflammation of intestines. Sensitivity to
sunlight. Decreased production of sperm.
In part B and C M4344 will be administered with cytotoxic chemotherapy
(carboplatin). There is extensive information on the side effect profiles of
this chemotherapeutic agent in human subjects with cancer which will be
explained to the subjects. Based on the mechanism of action of M4344, the
addition of M4344 to chemotherapy may increase the frequency and/or severity of
these side effects.
Frankfurter Strasse 250
Darmstadt 64293
DE
Frankfurter Strasse 250
Darmstadt 64293
DE
Listed location countries
Age
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 transplant or extensive radiotherapy to greater than 15%
of bone
marrow
10. Participation, or plan of participation, in another interventional clinical
study while taking
part in this Phase 1 study of M4344. Participation in an observational study
would be
acceptable
11. Any other condition which in the investigator*s opinion would not make the
subject a
good candidate for the clinical study, including:
a. History of human immunodeficiency virus-1 (HIV-1), HIV-2, or unresolved
hepatitis B or unresolved hepatitis C infection
b. High medical risk because of nonmalignant systemic disease including active
uncontrolled infection
c. Subjects who have been diagnosed with Li-Fraumeni Syndrome or with ataxia
telangiectasia
12. Part C only: Current malignancies of other types, with the exception of
adequately treated
cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell
carcinoma
of the skin; prior cancer that has been in remission for at least 3 years would
not be
excluded.
13. Current therapy:
a. Subjects receiving treatment with medications that are known to be strong
inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) that cannot be
discontinued at least 1 week before first dose of study drug and for the
duration of the study. Examples of strong CYP3A4 inhibitors or inducers are
provided in Table 9-1.
b. Subjects receiving treatment with proton-pump inhibitors that cannot be
discontinued at least 1 week before first dose of study drug and for the
duration of the study. Examples of proton-pump inhibitors are provided in
Table 9-1.
14. Subjects who cannot comply with restrictions for medications or food as
specified in
Table 9-1
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTREudraCT 2014-0-NL |
| ClinicalTrials.gov | NCT02278250 |
| CCMO | NL51432.056.14 |