This multicenter Phase I/II trial consists of two stages: a phase I stage in patients with
castration resistant prostate cancer in which the recommended phase II dose will be
determined for ipatasertib administered in combination with darolutamide; and a phase II
neoadjuvant stage in which patients with high risk prostate cancer and loss of PTEN
expression in the tumor tissue planning on undergoing prostatectomy receive ADT,
darolutamide, and ipatasertib for 24 weeks prior to planned surgery.
The proposed trial is a single arm, two stage trial looking for an efficacy signal in the
neoadjuvant setting in patients with PTEN-null tumors. The active therapy is a combination of
androgen deprivation therapy, darolutamide, and ipatasertib. Patients will be treated for 6
months prior to prostatectomy, since previous studies have shown that pCR+MRD rate is higher
with 6 months of ADT + abiraterone (24%) than 3 months (4%) (Taplan ME et al. J Clin Oncol.
2014;32(33):3705-15). Since the combination has not been evaluated before, a lead-in cohort
in patients with castration resistant prostate cancer will be performed to evaluate safety
and drug-drug interaction.
The lead-in cohort will enroll 6 patients to assess the safety of ipatasertib and
darolutamide. Ipatasertib has already been evaluated in combination with the AR pathway
inhibitors abiraterone and enzalutamide, where 400 mg was found to be safe. Therefore
patients will receive the expected final dose of darolutamide 600 mg BID and ipatasertib 400
mg daily. Toxicities will be monitored for 28 days, and blood samples will be drawn for
pharmacokinetic (PK) studies. If one or fewer patients experience a DLT the trial will
advance to the neoadjuvant setting. If two or more patients experience a DLT at 400 mg, the
dose will be reduced for already enrolled patients and another 6 patients will be enrolled to
evaluate darolutamide 600 mg BID and ipatasertib 200 mg daily.
PK evaluations will continue for a total of 6 months. Enrollment in the neoadjuvant cohort
can proceed before PK studies are complete.
Patients will have response evaluated at 12 weeks, including PSA response and radiographic
response per modified PCWG3. If there is progression on bone scan alone, patients should have
confirmatory bone scan in at least 6 weeks later. Patients will continue on therapy until the
time of progression.
Phase I Inclusion Criteria:
- Histologically confirmed prostate cancer
- Male and >= 18 years of age
- ECOG performance status of <= 2
- Castration resistant prostate cancer, defined as biochemical, radiographic, and/or
clinical progression despite castrate level of testosterone (<50 ng/dL). There is no
restriction on prior therapies for CRPC.
- Evaluable disease, with PSA >= 1.0 ng/ml and/or visible prostate cancer on imaging.
- Serum testosterone < 50 ng/dL
- Willing to undergo blood draws to measure PK levels
- Able to swallow pills
- Must have ability to understand and the willingness to sign a written informed consent
prior to receiving a subject ID number.
- Unless surgically sterile, sexually active patients must agree to use effective
barrier method and refrain from sperm donation during the study treatment and for 3
months after the end of study treatment.
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study
- Demonstrate adequate organ function as defined in the protocol; all screening labs to
be obtained within 14 days prior to registration.
Phase I Exclusion Criteria:
- Patients receiving systemic therapy for prostate cancer <= 21 days or 5 half-lives
(whichever is shorter) prior to starting study drug are not eligible.
-- NOTE: Patients must continue Androgen Deprivation Therapy, and patients can receive
bone supportive therapy.
- Histology of small cell carcinoma prostate cancer
- Any active infection requiring IV antibiotics
- Known additional malignancy that has a life-expectancy < 5 years.
- Clinically significant acute infection requiring systemic antibacterial, antifungal,
or antiviral therapy including:
- hepatitis B (known positive HBV surface antigen (HBsAg) result),
- hepatitis C, or
- human immunodeficiency virus (positive HIV 1/2 antibodies). ---NOTES: Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B
core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive
for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is
negative for HCV RNA. Subjects with HIV/AIDS with adequate antiviral therapy to
control viral load would be allowed if they are stable and have been on treatment
for >= 4 weeks prior to first dose of study drug(s). Subjects with viral
hepatitis with controlled viral load would be allowed while on suppressive
antiviral therapy.
- History of type I or type II diabetes mellitus requiring insulin.
- Any of the following within 6 months before registration: stroke, myocardial
infarction, severe/unstable anginal pectoris, coronary/peripheral artery bypass graft,
congestive heart failure New York Heart Association (NYHA) class III or IV.
- Congenital long QT syndrome or QTcF > 480 milliseconds
- Grade >= 2 uncontrolled or untreated hypercholesterolemia (>300 mg/dL) or
hypertriglyceridemia (>300 mg/dL)
- History of or active inflammatory bowel disease (IBD) or active bowel inflammation
(diverticulitis)
- Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic
infections (pneumocystis pneumonia or cytomegalovirus pneumonia)
- Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5
drug-elimination half-lives, whichever is longer, prior to initiation of study drug
- History of allergic reaction to darolutamide or ipatasertib.
- Any condition that in the opinion of the investigator would impair the patients'
ability to comply with study procedures.
Phase II Inclusion Criteria:
-Histologically-confirmed diagnosis of localized, untreated prostate cancer with high-risk
features. High-risk features is defined as:
- Two or more cores from prostate biopsy that are grade group 4 (Gleason score 4+4=8) or
higher, OR
- Stage T3-4 (by clinical exam or MRI), M0, and at least 2 cores from prostate biopsy
that are grade group 3 (Gleason score 4+3=7) or higher.
NOTE: Pathology confirmation of malignancy must be performed by the participating site
(i.e. reports should be issued by the participating site; if a subject's pathology report
was not issued by the participating site, archival tissue should be requested by the
participating site for internal pathology review.)
- Sufficient archival tissue (at least 2 cores) available for targeted sequencing and
immunohistochemistry to evaluate for PTEN loss using the Ventana SP218
immunohistochemistry assay at the local institution.
--The tumor evaluated for PTEN expression should be selected based on containing both
high grade and high volume of tumor content. The slide evaluated for PTEN expression
should be saved for confirmatory central review. Eligibility is based on local review.
- Measurable PSA
- Must have PTEN loss per local institution evaluation, defined as 50% or more of tumor
tissue being negative for PTEN expression on Ventana SP218 immunohistochemistry assay.
- Disease must be untreated and subject must be eligible for (per PI discretion) and
planning to undergo radical prostatectomy.
- Male and ≥18 years of age.
- ECOG performance status of ≤ 1 within 14 days prior to signing consent.
- CT or MRI of abdomen and pelvis and bone scan within ≤90 days prior to starting study
drug.
- Able to swallow pills
- Must have ability to understand and the willingness to sign a written informed consent
prior to starting study drug.
- Sexually active patients, unless surgically sterile, must agree to use effective
barrier method and refrain from sperm donation during the study treatment and for 3
months after the end of study treatment.
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study
- Demonstrate adequate organ function as defined in the protocol; all screening labs to
be obtained within 14 days prior to registration.
Phase II Exclusion Criteria:
- Histology of small cell carcinoma prostate cancer. Adenocarcinoma with neuroendocrine
features is allowed.
- Active infection requiring IV antibiotics
- Distant metastatic disease beyond N1 (regional) lymph nodes on conventional baseline
imaging studies within 90 days prior to signing consent.
- Known additional malignancy that has a life-expectancy < 10 years.
- Clinically significant acute infection requiring systemic antibacterial, antifungal,
or antiviral therapy including:
- tuberculosis (clinical evaluation that includes clinical history, physical
examination, and radiographic findings, and TB testing in line with local
practice),
- hepatitis B (known positive HBV surface antigen (HBsAg) result),
- hepatitis C, or
- human immunodeficiency virus (positive HIV 1/2 antibodies). NOTES: Patients with
a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is
negative for HCV RNA. Subjects with HIV/AIDS with adequate antiviral therapy to
control viral load would be allowed if they are stable and have been on treatment
for ≥ 4 weeks prior to first dose of study drug(s). Subjects with viral hepatitis
with controlled viral load would be allowed while on suppressive antiviral
therapy. Testing not required.
- Prior treatment of prostate cancer with: second generation androgen receptor (AR)
inhibitors, other investigational AR inhibitors or CYP17 enzyme inhibitor, radiation
therapy, surgery, or chemotherapy. First generation antiandrogen (e.g. bicalutamide)
for 28 days or fewer is allowed.
- Receipt of an investigational agent within <= 28 days prior to registration; or herbal
medications and marijuana products within <= 1 day prior to registration.
- Receipt of medications (e.g. finasteride, dutasteride) or agents that are likely to
alter serum PSA levels within <= 42 days or 5 half-lives prior to registration,
whichever is shorter.
- History of type I or type II diabetes mellitus requiring insulin.
- Any of the following within 6 months before registration: stroke, myocardial
infarction, severe/unstable anginal pectoris, coronary/peripheral artery bypass graft,
congestive heart failure New York Heart Association (NYHA) class III or IV.
- Congenital long QT syndrome or QTcF > 480 milliseconds
- Grade >= 2 uncontrolled or untreated hypercholesterolemia (>300 mg/dL) or
hypertriglyceridemia (>300 mg/dL)
- History of or active IBD or active bowel inflammation (diverticulitis)
- Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic
infections (pneumocystis pneumonia or cytomegalovirus pneumonia)
- Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5
drug-elimination half-lives, whichever is longer, prior to initiation of study drug
- History of allergic reaction to darolutamide or ipatasertib.
- Any condition that in the opinion of the investigator would impair the patients'
ability to comply with study procedures.
