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

• ClinicalTrials.gov Identifier: NCT04737109
• Recruitment Status: Recruiting
• First Posted: February 3, 2021
• Last Update Posted: October 27, 2021
• Sponsor: David VanderWeele
• Information provided by (Responsible Party): David VanderWeele, Big Ten Cancer Research Consortium

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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)

Eligibility Criteria

• 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.

Contacts and Locations

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

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

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

More 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
• Last Update Posted: October 27, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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