This is a Phase 1b/2a dose escalation and expansion, multi-center study to be conducted in 2
phases:
- Phase 1b
- Dose Escalation Part 1 (Doublet Therapy)
- Dose Escalation Part 2 (Triplet Therapy)
- Phase 2a
- Dose Expansion (Triplet Therapy)
Approximately 125 adult patients with histologically confirmed advanced solid tumors
requiring therapy will be enrolled in the study. It is expected that approximately 24
patients will be enrolled in up to 4 cohorts, 2 cohorts in Dose Escalation Part 1 and 2
cohorts in Dose Escalation Part 2, of up to 6 patients per cohort. Up to 98 additional
patients will be enrolled in the Dose Expansion phase of the study to achieve 88 evaluable
patients (i.e., received at least 1 dose of study drug(s) and have 1 evaluable post-baseline
modified RECIST v1.1 tumor response assessment; for mCRPC, assessment of soft tissue response
will be per modified RECIST v1.1 and bone progression assessment will be per PCWG3 guidelines
or discontinued treatment due to death, toxicity, or clinical progression) over 4 independent
expansion groups.In either phase (1b or 2a), patients discontinuing for reasons unrelated to
study treatment toxicity prior to completion of Cycle (C) 1 may be replaced to achieve the
number of required evaluable patients per cancer type following consultation with the
Sponsor. Data from each cohort in the Dose Escalation phase will be evaluated independently
for safety and dose limiting toxicities (DLTs) prior to dose escalation and again prior to
the Dose Expansion phase.
Inclusion Criteria:
- Advanced Solid Malignancies in Dose Escalation Parts 1 and 2:
- Histologically documented metastatic or locally advanced, incurable solid
malignancy.
- At least one prior line of systemic therapy for metastatic or locally advanced
disease.
- Advanced Triple Negative Breast Cancer (Dose Expansion):
- Histologically proven invasive breast carcinoma with triple-negative receptor
status.
- At least 1 but no more than 2 prior lines of chemotherapy for metastatic or
locally advanced disease.
- Advanced Hormone Receptor-Positive/Endocrine-Refractory Breast Cancer (Dose
Expansion):
- Histologically proven invasive breast carcinoma with hormone receptor+, HER2-
status.
- Only postmenopausal women are eligible. - Previously received at least 1 line of
aromatase inhibitor ± cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor therapy.
Prior combination therapies of AI or selective estrogen receptor degrader (SERD
[fulvestrant]) ± CDK 4/6 inhibitor or AI plus everolimus will be permitted. Up to
1 prior line of systemic chemotherapy for metastatic disease is allowed.
- Advanced Metastatic Castration-Resistant Prostate Cancer (Dose Expansion):
- Histologically or cytologically confirmed prostate adenocarcinoma or poorly
differentiated carcinoma of the prostate.
- Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0
nM). If a patient is being treated with LHRH agonists, this therapy must have
been initiated at least 4 weeks prior to treatment start and must be continued
throughout the study.
- Patients must have received ≥1 androgen receptor (AR) signaling inhibitors and
had disease progression RECIST v1.1 after no more than 1 prior chemotherapy for
mCRPC.
- Advanced Platinum-Resistant Ovarian Cancer (Dose Expansion):
- Histologically or cytologically confirmed diagnosis of metastatic, advanced, or
recurrent platinum-resistant epithelial ovarian, primary peritoneal or fallopian
tube cancer.
- Platinum-resistant ovarian cancer defined as disease progression following a
response within 180 days following the last administered dose of platinum
therapy. Patients who have lack of response (SD) or disease progression while
receiving the most recent platinum-based therapy are not eligible.
- Received up to 3 lines of systemic therapy for platinum-sensitive disease, with
the most recent regimen platinum-containing, and no prior systemic therapy for
platinum-resistant or refractory disease.
- General:
- Tumor tissue for mandatory pre-treatment and on-treatment biopsies.
- One or more tumors measurable on radiographic imaging defined by RECIST 1.1.
- Adult patients ≥18 years of age.
- ECOG performance status (PS) score of 0 or 1.
- Life expectancy of at least 12 weeks.
- Disease-free of active second/secondary or prior malignancies for ≥2 years, with
the exception of currently treated basal cell or squamous cell carcinoma of the
skin or carcinoma in-situ of the cervix or breast.
- Acceptable liver, renal, hematologic and coagulation function.
Exclusion Criteria:
- Hematologic malignancies or multiple myeloma.
- For the Dose Expansion cohorts the following cancers are not permitted:
- Any of the following pure histologies of ovarian cancer: germ cell, sex cord
stroma, carcinosarcoma, or sarcoma.
- Small cell or pure neuroendocrine prostate carcinoma that has not yet been
treated with at least one line of platinum-based chemotherapy (prostate
adenocarcinoma with immunohistochemical neuroendocrine differentiation but
without histological small cell that is naïve to platinum-based chemotherapy will
be allowed.)
- Inflammatory breast cancer.
- New York Heart Association Class III or IV cardiac disease, myocardial infarction
within the past 6 months, or unstable arrhythmia.
- Cardiac function:
- Known ejection fraction of <50% by gated radionuclide study (e.g., multi-gated
acquisition scan);
- Fridericia-corrected QT interval (QTcF) >470 msec (female) or >450 msec (male),
or history of congenital long QT syndrome;
- Any ECG abnormality, including pericarditis, that in the Investigator's opinion,
would preclude safe participation in the study.
- Active, uncontrolled bacterial, viral, or fungal infections within 7 days of study
entry requiring systemic therapy.
- Active autoimmune disease that has required systemic treatment in the past 2 years.
Replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of
systemic treatment.
- Known clinically important respiratory impairment.
- History of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
- History of interstitial lung disease.
- Clinically significant gastrointestinal disorders, such as perforation,
gastrointestinal bleeding, or diverticulitis.
- Known to be human immunodeficiency virus (HIV) positive or have hepatitis B surface
antigen (HBSAg) or hepatitis C antibodies (HCAb) unless hepatitis C virus (HCV) RNA is
undetected/negative.
- History of major organ transplant (i.e., heart, lungs, liver, and kidney).
- History of an allogeneic bone marrow transplant.
- History of an autologous bone marrow transplant within 90 days of study entry.
- Symptomatic central nervous system (CNS) malignancy or metastasis. Patients with
treated CNS metastases are eligible, provided their disease is radiographically
stable, asymptomatic, and they are not currently receiving corticosteroids and/or
anticonvulsants. Radiation must have been completed at least 14 days prior to study
entry. Screening of asymptomatic patients without a history of CNS metastases is not
required.
- Serious nonmalignant disease that could compromise protocol objectives in the opinion
of the Investigator and/or the Sponsor.
- Pregnant or nursing women.
