Trial Title:
A Single-Arm Phase II Study of Neoadjuvant Intensified Androgen Deprivation (Leuprolide and Abiraterone Acetate) in Combination With AKT Inhibition (Capivasertib) for High-Risk Localized Prostate Cancer With PTEN Loss
NCT ID:
NCT05593497
Condition:
High-Risk Prostate Cancer
Conditions: Official terms:
Prostatic Neoplasms
Abiraterone Acetate
Conditions: Keywords:
veterans
prostate cancer
PTEN protein
prostatectomy
neoadjuvant therapy
abiraterone acetate
capivasertib
leuprolide
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Eligible patients with high-risk prostate cancer exhibiting <= 10% PTEN staining by IHC
will be exposed to a 4-week run-in of iADT, followed by dedicated research biopsy of the
tumor to be used for correlative research, then treated with 16 weeks of combined iADT
with AKT inhibition (capivasertib). Patients will then undergo radical prostatectomy as
standard of care, with assessment of pathological response (pT0 or minimal residual
disease) via central pathology review.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Capivasertib
Description:
400 mg (2 tablets) BID given on an intermittent weekly dosing schedule. Patients will be
dosed on Days 1 to 4 in each week (4 days on, 3 days off). Treatment will be given in
combination with abiraterone for 16 weeks duration (+/- 1 week for surgery window).
Arm group label:
Single Arm
Intervention type:
Drug
Intervention name:
abiraterone acetate
Description:
Administered orally as tablets at a dosage of 1000 mg daily. To be administered with
prednisone 5mg po daily.
Subjects will be on concurrent GNRH agonist therapy (leuprolide, administered as standard
of care). Intensified androgen deprivation (iADT) consisting of abiraterone and
leuprolide will be administered for a 4 week run-in prior to addition of capivasertib.
Arm group label:
Single Arm
Summary:
The purpose of this study is to learn about how an investigational drug intervention
completed before doing prostate surgery (specifically, radical prostatectomy with lymph
node dissection) may help in treatment of high risk localized prostate cancers that are
most resistant to standard treatments. This is a phase II research study. For this study,
capivasertib, the study drug, will be taken with intensified androgen deprivation drugs
(iADT; abiraterone and leuprolide) prior to radical prostatectomy. This study drug
treatment will be evaluated to see if it is effective in shrinking and destroying
prostate cancer tumors prior to surgery and to further evaluate its safety prior to
prostate cancer surgery.
Detailed description:
Prostate cancer is the second leading cause of cancer deaths in men in the United States.
Prostate cancer treatment options are historically based on clinical stage, prostate
specific antigen (PSA) blood test, and tumor grade. High-risk prostate cancers treated
surgically commonly exhibit loss of the phosphatase and tensin homologue (PTEN) tumor
suppressor gene, which leads to increased activity of the AKT signaling pathway. PTEN
loss is associated with higher rates of prostate cancer recurrence, metastasis, and
cancer mortality. Manipulation of androgens and androgen receptor (AR) to reduce
mortality has been the focus of prostate cancer systemic therapy for decades; however,
PTEN loss is a lead mechanism for prostate cancer resistance to AR directed therapy and
development of castrate resistant prostate cancer. Pre-clinical research identified a
reciprocal feedback regulation between the PTEN/AKT signaling axis and the Androgen
Receptor (AR) signaling axis. Thus, blockade of both pathways may be necessary in tumors
with PTEN loss.
This study will change standard localized treatment (radical prostatectomy alone) by
conducting a single arm Phase II trial combining intensified androgen deprivation (iADT;
abiraterone and leuprolide) with an AKT inhibitor (capivasertib) prior to radical
prostatectomy among high-risk localized prostate cancers with PTEN loss. The goal is that
early precision treatment of aggressive disease will result minimal residual cancer at
the time of prostatectomy, and subsequently improved cancer outcomes.
Eligible patients with high-risk prostate cancer exhibiting 10% PTEN staining by IHC will
be exposed to a 4-week run-in of iADT, followed by dedicated research biopsy of the tumor
to be used for correlative research, then treated with 16 weeks of combined iADT with AKT
inhibition (capivasertib). Patients will then undergo radical prostatectomy as standard
of care, with assessment of pathological response (pT0 or minimal residual disease) via
central pathology review.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Informed Consent: provision of signed informed consent, which includes compliance
with the requirements and restrictions listed in the informed consent form (ICF) and
in this protocol.
2. Age greater than or equal to 18 years. Members of all races and ethnic groups will
be included.
3. Participants must have histologically confirmed non-metastatic adenocarcinoma of the
prostate
4. (a) Any one of the following three high risk features:
- Gleason sum >7 (ISUP Grade Group >3)
- Clinical stage T3 (resectable), per AJCC Cancer Staging Manual, 8th ed.
- PSA > 20 ng/ml oSubjects who meet high risk criteria solely by PSA (i.e., stage
2 cm in diameter on pelvic CT scan (scan only required
in patients with a PSA > 20 ng/ml)
7. Prostatectomy with extended lymph node dissection planned as primary therapy.
- The subject had a discussion with a clinician about other options, such as
radiotherapy, and elected to undergo surgical treatment.
- The subject has been offered consultation with radiation oncology and declined
consultation or radiation treatment, or determined it was not in best medical
interest
8. Be willing to provide tissue from a diagnostic biopsy core or excisional biopsy of a
tumor lesion obtained up to 6 months/180 days prior to initiation of treatment on
Day 1. Subjects for whom samples cannot be provided (e.g., inaccessible or subject
safety concern) may submit an older archived specimen only upon agreement from the
Sponsor-Investigator.
9. Tumor tissue must be provided for biomarker analysis. PTEN IHC staining must be less
than or equal to 10% as determined by the central lab. If insufficient tumor tissue
content is provided for analysis, acquisition of additional archived tumor tissue
(block and /or slides) for the biomarker analysis is required.
10. Have a performance status of 0 or 1 on the ECOG Performance Scale with no
deterioration over the previous 2 weeks prior to baseline or day of first dosing.
11. Life expectancy of greater than 10 years per the treating physician.
12. Minimum body weight of 45 kg with minimum Body Mass Index (BMI) of 18.5
13. Non-sterile men who are not totally sexually abstinent (i.e., refraining from
heterosexual intercourse during the entire period of risk associated with study
interventions) and intend to be sexually active with a women of childbearing
potential partner must use a condom upon entering the study and until 16 weeks after
the last dose of capivasertib. Contraception should be considered in females'
partners of men taking capivasertib who are of childbearing potential
14. Able and willing to swallow and retain oral medication
15. Demonstrate adequate organ function as defined by laboratory parameters including
ANC, platelets, hemoglobin, transaminases, albumin, hemoglobin A1C, CrCl or eGFR,
PTT and INR (unless anticoagulated, then therapeutic range is acceptable). All
screening labs should be performed within 30 days of treatment initiation
Exclusion Criteria:
1. As judged by the investigator, any evidence of diseases (such as severe or
uncontrolled systemic diseases, including uncontrolled hypertension, renal
transplant and active bleeding diseases, uncontrolled pulmonary, renal, or hepatic
dysfunction, uncontrolled infection, cardiac disease) which, in the investigator's
opinion, makes it undesirable for the participant to participate in the study or
that would jeopardize compliance with the protocol.
2. Any other disease, physical examination finding, or clinical laboratory finding
that, in the investigator's opinion, gives reasonable suspicion of a disease or
condition that contraindicates the use of an investigational drug, may affect the
interpretation of the results, render the patient at high risk from treatment
complications or interferes with obtaining informed consent.
3. Known to have active hepatitis infection, positive hepatitis C antibody, hepatitis B
virus surface antigen or hepatitis B virus core antibody, at screening. Known to
have human immunodeficiency virus (HIV) with a CD4+ T-cell count < 350 cells/uL or a
history of an acquired immunodeficiency syndrome (AIDS)-defining opportunistic
infection within the past 12 months. Known to have active tuberculosis infection
(clinical evaluation that may include clinical history, physical examination and
radiographic findings, or tuberculosis testing in line with local practice).
Known history of drug or alcohol abuse within 6 months of screening.
4. Prior prostate cancer treatment including:
- Anti-androgen therapy including orchiectomy, LHRH therapy, abiraterone,
ketoconazole, estrogen therapy (Short-term ADT allowed, less than or equal to 2
months)
- Radiation (external beam or brachytherapy)
- Cytotoxic chemotherapy
- Focal or ablative therapy
- Any experimental therapy for treatment of prostate cancer.
5. History of another primary malignancy except for malignancy treated with curative
intent with no known active disease greater than or equal to 5 years before the
first dose of study intervention and of low potential risk for recurrence.
Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of
the skin that has undergone potentially curative therapy
6. Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive
ECGs
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG (e.g., complete left bundle branch block, third-degree heart block)
- Medical history significant for arrhythmia (e.g., multifocal premature
ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which
is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or
uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained
ventricular tachycardia. Participants with atrial fibrillation controlled by
medication or arrhythmias controlled by pacemakers may be permitted to enter
the study
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, potential for torsades de pointes,
congenital long QT syndrome, family history of long QT syndrome or unexplained
sudden death under 40 years of age, or any concomitant medication known to
prolong the QT interval
- Clinically significant heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or
NYHA or Class II to IV heart failure or cardiac ejection fraction measurement
of < 50%
- Experience of any of the following procedures or conditions in the preceding 6
months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
infarction, angina pectoris, congestive heart failure NYHA Grade less than or
equal to 2
- Uncontrolled hypotension - systolic blood pressure (SBP) <90 mmHg and/or
diastolic blood pressure (DBP) <50 mmHg
- Uncontrolled hypertension (SBP greater than or equal to 160 mmHg or DBP greater
than or equal to 95 mmHg).
- Cardiac ejection fraction outside institutional range of normal or <50%
(whichever is higher) as measured by echocardiogram (or multiple-gated
acquisition [MUGA] scan if an echocardiogram cannot be performed or is
inconclusive).
7. Clinically significant abnormalities of glucose metabolism as defined by any of the
following:
- Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiring
insulin treatment
- HbA1c greater than or equal to 8.0% (63.9 mmol/mol)
8. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to
swallow the formulated product, or previous significant bowel resection that would
preclude adequate absorption, distribution, metabolism, or excretion of capivasertib
and abiraterone.
9. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
10. Previous allogeneic bone marrow transplant or solid organ transplant
11. Received major surgery within 6 weeks prior to screening, or significant traumatic
injury within 4 weeks of the first dose of study intervention or an anticipated need
for major surgery during the study except for prostatectomy; they must have
recovered adequately from the toxicity and/or complications from the intervention
prior to starting therapy.
12. Is currently participating and receiving study therapy, or has participated in a
study of an investigational agent or study drugs within 30 days or 5 half-lives
(whichever is longer) of the first dose of study treatment
13. Has had a prior anti-cancer monoclonal antibody (mAb) within 30 days prior to study
Day 1 or who has not recovered (i.e., less than or equal to Grade 1 or at baseline)
from adverse events due to agents administered more than 30 days earlier.
14. Has had prior chemotherapy, immunotherapy, targeted small molecule therapy,
immunosuppressant medication (other than corticosteroids), or radiation therapy
within 30 days prior to study Day 1, or who has not recovered (i.e., less than or
equal to Grade 1 or at baseline) from adverse events due to a previously
administered agent.
Note: Subjects with less than or equal to Grade 2 neuropathy are an exception to
this criterion and may qualify for the study if ECOG 0-1.
Note: A longer washout may be required for drugs with a long half-life (e.g., 30
days or 5 half-lives, whichever is longer)
15. Treatment with any of the following:
- Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment
- Potent inhibitors or inducers of CYP3A4 within 2 weeks before the start of
study treatment (3 weeks for St John's wort), or sensitive substrates of
CYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 week
before the start of study treatment
- Drugs known to prolong the QT interval within 5 half-lives of the first dose of
study treatment
- Any concomitant medication that may interfere with abiraterone safety and
efficacy based on the prescribing information of abiraterone and local clinical
guidelines
16. History of hypersensitivity to active or inactive excipients of capivasertib,
abiraterone, or drugs with a similar chemical structure or class.
17. Any restriction or contraindication based on the local prescribing information that
would prohibit the use of abiraterone and leuprolide.
18. Is unable to undergo research related biopsy as this is necessary to complete
translational study objectives.
19. Judgment by the investigator that the participant should not participate in the
study if the participant is unlikely to comply with study procedures, restrictions
and requirements.
Gender:
Male
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
VA Greater Los Angeles Healthcare System, West Los Angeles, CA
Address:
City:
West Los Angeles
Zip:
90073-1003
Country:
United States
Status:
Recruiting
Contact:
Last name:
Matthew B Rettig, MD
Phone:
310-478-3711
Phone ext:
44761
Email:
Matthew.rettig@va.gov
Contact backup:
Last name:
Samantha M Tran
Phone:
3104783711
Phone ext:
44917
Email:
Samantha.Tran@va.gov
Facility:
Name:
James J. Peters VA Medical Center, Bronx, NY
Address:
City:
Bronx
Zip:
10468-3904
Country:
United States
Status:
Recruiting
Contact:
Last name:
Izak Faiena, MD
Email:
izak.faiena@va.gov
Contact backup:
Last name:
Amelia Kiliveros
Email:
amelia.kiliveros@va.gov
Facility:
Name:
VA Portland Health Care System, Portland, OR
Address:
City:
Portland
Zip:
97207-2964
Country:
United States
Status:
Recruiting
Contact:
Last name:
Ryan P Kopp, MD
Phone:
503-220-8262
Phone ext:
56128
Email:
ryan.kopp@va.gov
Contact backup:
Last name:
Laura Onstad, RN
Phone:
(503) 721-1060
Email:
laura.onstad@va.gov
Investigator:
Last name:
Ryan P Kopp, MD
Email:
Principal Investigator
Facility:
Name:
South Texas Health Care System, San Antonio, TX
Address:
City:
San Antonio
Zip:
78229-4404
Country:
United States
Status:
Terminated
Facility:
Name:
VA Puget Sound Health Care System Seattle Division, Seattle, WA
Address:
City:
Seattle
Zip:
98108-1532
Country:
United States
Status:
Recruiting
Contact:
Last name:
Robert B Montgomery, MD
Phone:
206-277-6878
Email:
rbmontgo@uw.edu
Contact backup:
Last name:
Makayla L Dejong
Phone:
2062774527
Email:
Makayla.Dejong@va.gov
Start date:
May 31, 2024
Completion date:
August 1, 2027
Lead sponsor:
Agency:
VA Office of Research and Development
Agency class:
U.S. Fed
Source:
VA Office of Research and Development
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05593497
