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

A Single Arm, Phase I/II Trial of Neoadjuvant Androgen Deprivation, Darolutamide, and Ipatasertib in Men With Localized, High Risk Prostate Cancer Big Ten Cancer Research Consortium BTCRC-GU19-404

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.

Study Overview

• Status: Terminated
• Conditions: Castrate Resistant Prostate Cancer
• Intervention / Treatment: Drug: Ipatasertib; Drug: Darolutamide; Drug: Androgen Deprivation Therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and Bren Simon Comprehensive Cancer Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Eligibility Criteria Approximately 26-38 patients with prostate cancer will be enrolled in this study. This includes 6-18 patients in the Phase I de-escalation cohort with metastatic or nonmetastatic castration resistant prostate cancer, and 20 patients in the Phase II neoadjuvant cohort with high risk localized or locally advanced prostate cancer that has PI3K pathway activation.

• For the Phase I de-escalation cohort, the patient must have castration resistant prostate cancer (metastatic or non-metastatic), as defined by PCWG3.

• For the Phase II neoadjuvant cohort, the patient must be a candidate for radical prostatectomy at the time of enrollment and be planning to undergo this procedure. The patient must have a histologically-confirmed diagnosis of localized, untreated prostate cancer with high risk features and must have sufficient archival tissue (at least 2 cores) available for targeted sequencing and immunohistochemistry (IHC). The tumor must have PI3K pathway activation. This can be determined by IHC, in which case at least 50% of the tumor tissue evaluated must be negative for PTEN expression by immunohistochemistry on local review. Alternatively, qualifying alteration in PTEN, PIK3CA, or AKT1 on next generation sequencing (NGS) is also acceptable to be eligible, regardless of PTEN expression. If the patient qualifies based on NGS results, IHC must still be performed.

  • 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.

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 (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

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. 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.

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. 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.

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 < 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I De-Escalation Cohort: ADT + Ipatasertib + Darolutamide; Cycle 0 Days 1-7: Ipatasertib Monotherapy + Androgen Deprivation Therapy (ADT) Cycle 1+: Ipatasertib + Darolutamid + ADT	Drug: Ipatasertib; Ipatasertib; Drug: Darolutamide; Darolutamide; Drug: Androgen Deprivation Therapy; ADT per institutional standards; Other Names: ADT
Experimental: Phase II: ADT + Ipatasertib + Darolutamide; All Cycles: Ipatasertib + Darolutamide + ADT	Drug: Ipatasertib; Ipatasertib; Drug: Darolutamide; Darolutamide; Drug: Androgen Deprivation Therapy; ADT per institutional standards; Other Names: ADT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase II: Pathological Complete Response (pCR) Rate	Combined rate of pathologic complete response (pCR) (defined as absence of pathologic disease on hematoxylin and eosin (H&E) stain (ypT0)), or with presence of minimal residual disease (<5 mm linearly)	From C1D1 until death.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Dose-Limiting Toxicities	A summary of all dose-limiting toxicities experienced by Phase I subjects within the first cycle (28 days) of treatment, as defined in the study protocol.	Until the completion of cycle 1, 28 days
Phase II - Two Year Biochemical Recurrence-free Survival	Two year biochemical recurrence-free survival (PSA ≤ 0.2 ng/mL) will be measured in men with high risk, localized, prostate cancer that is lacking PTEN	From C1D1 until death or up to a maximum of 24 months
Phase II: Rate of PSA0	Rate of PSA0 (undetectable PSA on local institutions laboratory testing with testosterone recovery and no additional therapy) will be measured in men with high risk, localized, prostate cancer that is lacking PTEN.	From C1D1 until death.

Collaborators and Investigators

• Sponsor: David VanderWeele
• Investigators: Principal Investigator: David VanderWeele, MD\Phd, Northwestern University

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2021
• Primary Completion (Actual): August 15, 2022
• Study Completion (Actual): August 15, 2022

Study Registration Dates

• First Submitted: January 29, 2021
• First Submitted That Met QC Criteria: February 2, 2021
• First Posted (Actual): February 3, 2021

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: October 23, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: neoadjuvant; prostate cancer; high risk; PTEN loss; darolutamide; ipatasertib
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protein Kinase Inhibitors; Androgens; Ipatasertib
• Other Study ID Numbers: BTCRC-GU19-404

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No