A Phase I Study of MK-4827 in Patients With Advanced Solid Tumors or Hematologic Malignancies
- For Part A, participants must have a cytologically- or histologically-confirmed
metastatic or locally advanced solid tumor for which standard therapy does not exist
or the participants have refused standard therapy.
- For Part B, participants must have a cytologically- or histologically-confirmed
locally advanced or metastatic prostate cancer for which standard therapy does not
exist or the participants have refused standard therapy or sporadic (not known to
have BRCA1 or BRCA2 gene mutations) recurrent platinum resistant high grade serous
ovarian, primary peritoneal, or fallopian tube cancer. Participants who progressed
while receiving a platinum-containing regimen are not eligible. Participants with
ovarian cancer must have at least one measurable lesion (at least 15 mm in one
dimension) or a cancer antigen (CA)-125 value twice the institutional upper limit of
- For Part B, participants must have archival tumor tissue available.
- For Part C, participants must have a cytologically- or histologically-confirmed
diagnosis of T-PLL or B-cell CLL. Participants with T- PLL must have progressed after
receiving alemtuzumab. Participants with CLL must have been refractory to or
progressed within 12 months following a fludarabine-containing regimen or have
received at least 2 prior therapies (before or after the fludarabine containing
- For Part D, participants must have:
- a cytologically- or histologically-confirmed metastatic or locally advanced
adenocarcinoma of the colon or rectum (mCRC) and evidence of phosphate and tensin
homolog (PTEN) deficiency. Participants must have received at least 1 prior
5-fluoruracil (5-FU)-based combination chemotherapy regimen for mCRC, containing
oxaliplatin or irinotecan. Participants must have measurable disease.
- a cytologically- or histologically-confirmed persistent or recurrent endometrial
carcinoma and measurable disease. Participants may not have had more than 1 prior
- a cytologically- or histologically-confirmed metastatic or locally advanced sporadic
(not known to have a germline BRCA1 or BRCA2 mutation) partially platinum-sensitive
recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal
cancer. Participants who cannot receive platinum due to allergy or toxicity are
eligible. Participants with ovarian cancer may have received non-platinum containing
chemotherapy between their last platinum-containing regimen and enrolling in this
study. Participants must have measurable disease or an elevated CA-125 (at least 2
times the institutional upper limit of normal).
- a cytologically- or histologically-confirmed metastatic or locally advanced carcinoma
of the breast that either lacks expression of the estrogen receptor (ER),
progesterone receptor (PR) and HER2 (triple negative [TN]) or is ER and/or PR+ .
Participants with locally advanced disease must have recurrent or progressive disease
that is not suitable for treatment with curative intent. Participants with ER
positive disease must have been treated with at least one line of hormonal therapy
for recurrent/progressive disease or have been on hormonal therapy at the time of
recurrence/progression. Participants with either ER+ or TN tumors may not have had
more than 1 line of chemotherapy for treatment of recurrent disease. If participants
received adjuvant chemotherapy they must have had a disease-free interval of at least
6 months from the completion of adjuvant chemotherapy. Participants must have
- Participant must have performance status ≤2 on the ECOG Performance Scale.
- Participant must have adequate organ function.
- Female participants of childbearing potential must have a negative pregnancy test
within 72 hours prior to receiving the first dose of study medication.
- Participants with prostate cancer must continue on luteinizing-hormone-releasing
hormone (LHRH) analogues if they have not had an orchiectomy to achieve a sustained
baseline serum testosterone < 50 ng/dL.
- Participant who has had chemotherapy, radiotherapy, hormonal or biological therapy
within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to first dose of study
- Participant is currently participating or has participated in a study within 30 days
or 5 half lives (which ever is longer) of administration of an investigational agent
or within 30 days of participating in a study using an investigational device.
- Participants who have received bevacizumab may enter the trial 4 weeks after their
last dose of bevacizumab if all bevacizumab-related toxicities have resolved.
- Participant with a history of a prior malignancy with the exception of cervical
intraepithelial neoplasia; basal cell carcinoma of the skin; adequately treated
localized prostate carcinoma with prostatic-specific antigen (PSA) <1.0; or who has
undergone potentially curative therapy with no evidence of that disease for five
years, or who is deemed at low risk for recurrence by his/her treating physician.
- Participants with known central nervous system (CNS) metastases and/or carcinomatous
meningitis are excluded.
- Participant with a known primary central nervous system tumor.
- Participant has known hypersensitivity to the components of study drug or its
- Participant has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.
- Participant is, at the time of signing informed consent, a regular user (including
"recreational use") of any illicit drugs or had a recent history (within the last
year) of drug or alcohol abuse.
- Participant is pregnant or breast feeding, or expecting to conceive or father
children within the projected duration of the study.
- Participant is known to be Human Immunodeficiency Virus (HIV)-positive.
- Participant has known history of Hepatitis B or C.
- Participant has symptomatic ascites or a symptomatic pleural effusion.
- Participant has participated in a clinical trial with a known or putative PARP
- Participants with T-PLL or CLL with active autoimmune hemolytic anemia.
- Participants may not have had therapy with corticosteroids at greater than or equal
to 20 mg/day prednisone equivalent within 2 weeks prior to the first dose of