Neoadjuvant Androgen Deprivation, Darolutamide, and Ipatasertib in Men With Localized, High Risk Prostate Cancer

NCT ID: NCT04737109

Last Updated: 2023-11-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-13
• Study Completion Date: 2022-08-15

Brief Summary

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 PI3K pathway activation in the tumor tissue planning on undergoing prostatectomy receive ADT, darolutamide, and ipatasertib for 24 weeks prior to planned surgery.

Detailed Description

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 in the Phase I portion 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 at least 6 weeks later. Patients will continue on therapy until the time of progression.

Conditions

Castrate Resistant Prostate Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase I De-Escalation Cohort: ADT + Ipatasertib + Darolutamide

Cycle 0 Days 1-7: Ipatasertib Monotherapy + Androgen Deprivation Therapy (ADT) Cycle 1+: Ipatasertib + Darolutamid + ADT

Group Type: EXPERIMENTAL

Ipatasertib

Intervention Type: DRUG

Ipatasertib

Darolutamide

Intervention Type: DRUG

Darolutamide

Androgen Deprivation Therapy

Intervention Type: DRUG

ADT per institutional standards

Phase II: ADT + Ipatasertib + Darolutamide

All Cycles: Ipatasertib + Darolutamide + ADT

Group Type: EXPERIMENTAL

Ipatasertib

Intervention Type: DRUG

Ipatasertib

Darolutamide

Intervention Type: DRUG

Darolutamide

Androgen Deprivation Therapy

Intervention Type: DRUG

ADT per institutional standards

Interventions

Ipatasertib

Ipatasertib

Intervention Type: DRUG

Darolutamide

Darolutamide

Intervention Type: DRUG

Androgen Deprivation Therapy

ADT per institutional standards

Intervention Type: DRUG

Other Intervention Names

ADT

Eligibility Criteria

Inclusion Criteria

• Qualifying mutations include changes in AKT1 at residues E17, L52, or Q79; in PIK3CA at residues R88, G106, K111, G118, N345, E542, E545, Q546, M1043, H1047, or G1049; in PTEN a R130Q/C/H substitution or a deletion, frameshift, or introduction of early stop codon. The assay must be a CLIA-certified assay, and a copy of the report must be provided.

• 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 (nmCRPC) or visible prostate cancer on imaging (mCRPC).
• 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.
• Hematological

--Hemoglobin (Hgb): >/= 9 g/dL

• Absolute Neutrophil Count (ANC): >/= 1,500/uL
• Platelet count: >/= 100,000/uL
• Renal --Creatinine: </= 2 x upper limit of normal (ULN)
• Hepatic

--Bilirubin: </= 1.5 ULN or Gilbert's syndrome with normal direct bilirubin

• Aspartate aminotransferase (AST) </= 2.5 x ULN
• Alanine aminotransferase (ALT): </= 2.5 x ULN
• Blood sugar

• HbA1C: </= 7.5%
• Fasting glucose</= 150 mg/dL

-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. Next generation sequencing is also acceptable to be eligible regardless of IHC result, but there must also be sufficient tissue to evaluate for PTEN by IHC.

--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 evidence of PI3K pathway activation. This can be by demonstrating PTEN loss per local institution evaluation, defined as 50% or more of tumor tissue being negative for PTEN expression on Ventana SP218 immunohistochemistry assay. Alternatively, qualifying alteration in PTEN, PIK3CA, or AKT1 on next generation sequencing is also acceptable to be eligible, regardless of PTEN expression.

--Qualifying mutations include changes in AKT1 at residues E17, L52, or Q79; in PIK3CA at residues R88, G106, K111, G118, N345, E542, E545, Q546, M1043, H1047, or G1049; or in PTEN a R130Q/C/H substitution, or a deletion, frameshift, or introduction of early stop codon. The assay must be a CLIA-certified assay, and a copy of the report must be provided.

• 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.

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. Adenocarcinoma with neuroendocrine features is allowed.
• Any active infection requiring IV antibiotics
• Known additional malignancy that has a life-expectancy < 2 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.

• 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 < 5 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

David VanderWeele

OTHER

Sponsor Role: lead

Responsible Party

David VanderWeele

Associate Professor, Medicine - Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

David VanderWeele, MD\Phd

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Locations

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Indianapolis, Indiana, United States

Penn State Cancer Institute

Hershey, Pennsylvania, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

BTCRC-GU19-404

Identifier Type: -

Identifier Source: org_study_id