Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04737109
Recruitment Status : Recruiting
First Posted : February 3, 2021
Last Update Posted : October 27, 2021
Sponsor:
Information provided by (Responsible Party):
David VanderWeele, Big Ten Cancer Research Consortium

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

Condition or disease Intervention/treatment Phase
Castrate Resistant Prostate Cancer Drug: Ipatasertib Drug: Darolutamide Drug: Androgen Deprivation Therapy Phase 1 Phase 2

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 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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 13, 2021
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

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 Name: 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 Name: ADT




Primary Outcome Measures :
  1. Pathological Complete Response (pCR) Rate [ Time Frame: After six cycles (6 months, each cycle is 28 days) ]
    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)


Secondary Outcome Measures :
  1. Summary of Grade 3 and 4 toxicities [ Time Frame: From enrollment until 30 days after the completion of six cycles or withdrawal from study (up to 7 months, each cycle is 28 days) ]
    Grade 3 and 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5

  2. 2 year Biochemical Recurrence-free Survival [ Time Frame: From enrollment up to two years ]
    Two year biochemical recurrence-free survival (PSA ≤ 0.2 ng/mL)

  3. Rate of PSA0 [ Time Frame: From enrollment up to two years ]
    Rate of PSA0 (undetectable PSA on local institutions laboratory testing with testosterone recovery and no additional therapy)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Subject's must be biologically male to participate in this study
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04737109


Contacts
Layout table for location contacts
Contact: David VanderWeele, MD, PhD 312-926-2413 david.vanderweele@northwestern.edu
Contact: Rae Richards 317-634-5842 ext 38 rrichards@hoosiercancer.org

Locations
Layout table for location information
United States, Illinois
Northwestern University Feinberg School of Medicine Recruiting
Chicago, Illinois, United States, 60611
Contact: Silvana Nicholas    312-695-0620    silvana.poggi@northwestern.edu   
Principal Investigator: David Vanderweele, MD         
Sponsors and Collaborators
David VanderWeele
Investigators
Layout table for investigator information
Principal Investigator: David VanderWeele, MD\Phd Northwestern University
Layout table for additonal information
Responsible Party: David VanderWeele, Assistant Professor, Hematology and Oncology Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Big Ten Cancer Research Consortium
ClinicalTrials.gov Identifier: NCT04737109    
Other Study ID Numbers: BTCRC-GU19-404
First Posted: February 3, 2021    Key Record Dates
Last Update Posted: October 27, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by David VanderWeele, Big Ten Cancer Research Consortium:
prostate cancer
high risk
neoadjuvant
PTEN loss
darolutamide
ipatasertib
Additional relevant MeSH terms:
Layout table for MeSH terms
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs