IRB Study Number 22-696
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective(s) & Hypothesis(es)
1) To evaluate the safety and tolerability of the pembrolizumab combination therapy.
2) To estimate PSA response rate of the pembrolizumab combination therapy.
3) To estimate the objective response rate (ORR) based on RECIST 1.1 assessed by BICR.
Secondary Objective(s) & Hypothesis(es)
(1) To estimate time to PSA progression.
(2) To estimate the objective response rate (ORR) based on PCWG3-modified RECIST 1.1 criteria assessed by BICR.
(3) To estimate radiographic progression-free survival (rPFS) based on Prostate Cancer Working Group 3 (PCWG3)-modified RECIST 1.1 assessed by BICR.
(4) To estimate overall survival (OS).
(5) To estimate the duration of response (DOR) based on a) RECIST 1.1 and b) PCWG3-modified RECIST 1.1 assessed by BICR.
(6) To estimate the disease control rate (DCR) based on a) RECIST 1.1 and b) PCWG3-modified RECIST 1.1 assessed by BICR.
(7) For Cohort A (pembrolizumab + olaparib) only, to estimate the composite response rate defined as any one of the following:
Response according to RECIST 1.1 assessed by BICR.
PSA response rate, defined as a reduction in the PSA level of 50% or more from baseline measured twice at least 3 weeks apart.
Conversion in the circulating tumor cell (CTC) count, defined as a reduction in the number of CTCs from 5 cells or more per 7.5 mL of blood at baseline to less than 5 cells per 7.5 mL during treatment (another sample will be collected 6 weeks later at a regularly scheduled visit to confirm response).
Inclusion Criteria
Be willing and able to provide documented informed consent/assent for the trial. The subject may also provide consent/assent for FBR. However, the subject may participate in the main trial without participating in FBR.
Be ≥18 years of age on day of providing documented informed consent.
Histology:
a. For Cohorts A, B, C, D, E, G: Have histologically- or cytologically-confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report and confirmed by the investigator.
b. For Cohorts F, H, I: Have t-NE or de novo metastatic prostate cancer defined by ≥1% neuroendocrine cells that are located in discrete regions of a recent biopsy specimen from a metastasis. Histology is to be initially determined by the investigational site. Neuroendocrine histology must then be confirmed by central histology review prior to enrollment. Subjects with t-NE must have prior histologic evidence of adenocarcinoma of the prostate gland by investigator report. (Note: The term de novo metastatic prostate cancer defines a group of subjects who developed metastatic neuroendocrine prostate cancer without a prior history of adenocarcinoma of the prostate. A limited number of such subjects with de novo mixed neuroendocrine/adenocarcinoma or pure neuroendocrine carcinoma will be allowed on study after approval by the Sponsor documented by a Sponsor consultation form). For important procedural requirements for biopsies, please see Section 7.1.2.8.
- For all cohorts: Have provided tumor tissue from a site not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed; other exceptions may be considered after Sponsor consultation). Adequacy of these specimens for biomarker analysis will be evaluated by a central laboratory prior to enrollment.
Cohorts A, E, & G: A core or excisional biopsy from soft tissue or a bone biopsy is required. A biopsy from soft tissue is preferred. In lieu of a soft tissue biopsy, a bone biopsy is permitted. Biopsies must have been performed within 1 year of screening and after developing mCRPC to be eligible for the study. Biopsies can be newly obtained biopsies or archival specimens that were obtained within this time frame. If several biopsies were performed within this time frame, the most recent biopsy should be submitted if possible. See the Procedures Manual for further details about eligible biopsy specimen types. A second, older specimen should also be provided for these subjects, if available.
Cohort B: An archival tumor tissue sample or tumor tissue from a fresh core or excisional biopsy from soft tissue is required.
Cohorts C & D: Subjects with soft tissue disease must provide a core or excisional biopsy from a soft tissue lesion if clinically accessible. In addition to the biopsy, an archival specimen should also be provided if one is available. The biopsy must be performed within 1 year of screening and after developing mCRPC. If soft tissue disease cannot be biopsied, then an archival specimen is required. For subjects with bone metastasis only, an archival tumor tissue specimen must be provided.
Cohorts F, H, & I (Neuroendocrine Cohorts):
A core or excisional biopsy from soft tissue or a bone biopsy is required. A biopsy from soft tissue is preferred. In lieu of a soft tissue biopsy, a bone biopsy is permitted. Tumor blocks are preferred. Biopsies must have been performed within 1 year of screening and after developing mCRPC and demonstrate neuroendocrine histology as defined above under “histology” to be eligible for the study. For de novo metastatic neuroendocrine prostate cancer patients, biopsies must be performed within 1 year of screening. Biopsies can be newly obtained biopsies or archival specimens that were obtained within this time frame. If several biopsies were performed within this time frame, the most recent biopsy should be submitted if possible. If available, a second, older specimen should also be provided for these subjects. See the Procedures Manual for further details about eligible biopsy specimen types and processing instructions.
- Have prostate cancer progression within 6 months prior to screening, as determined by the investigator, by means of one of the following: Note: Subjects with de novo neuroendocrine prostate cancer will not need to provide evidence of progression within 6 months.
a. PSA progression using local laboratory values as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL – See Section 7.1.2.9 – Prostate-specific Antigen Assessment for further details.
b. Radiographic disease progression in soft tissue based on RECIST 1.1 criteria with or without PSA progression.
c. Radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression. Note: Radiographs must be collected and transmitted to the central imaging vendor at study entry. Note: Subjects must present with 1 or more lesions outside of the prostate visible on imaging (bone or soft tissue). Subjects with PSA progression alone without such lesions at study entry are not eligible for inclusion in the trial.
- Have progression under the following conditions if the subject received anti-androgen therapy prior to enrollment:
a. Evidence of progression >4 weeks since last flutamide treatment.
b. Evidence of progression >6 weeks since last bicalutamide or nilutamide treatment.
Have ongoing androgen deprivation with serum testosterone <50 ng/dL (<1.7 nM). If the subject is currently being treated with luteinizing hormone-releasing hormone agonists or antagonists (subjects who have not undergone an orchiectomy), this therapy must have been initiated at least 4 weeks prior to first dose of trial treatment and treatment must be continued throughout the study for all cohorts. Note: Subjects with de novo metastatic NE prostate cancer will not be required to have been previously treated with ADT. ADT must be started in these participants by the time of treatment allocation/randomization.
Subjects receiving bone resorptive therapy (including, but not limited to, bisphosphonate or receptor activator of nuclear factor kappa-β ligand inhibitor) must have been on stable doses for ≥4 weeks prior to first dose of trial treatment.
Subjects are eligible to participate if they agree to contraception as described below during the intervention period starting with the first dose of study therapy. The length of time required to continue contraception after the last dose of study intervention for each study intervention is as follows:
o olaparib 95 days
o docetaxel 95 days
o enzalutamide 30 days
o abiraterone acetate 7 days
o lenvatinib 7 days
o carboplatin/etoposide 95 days
Note: For MK-7684A, no contraception measures are required during and after the intervention period.
Refrain from donating sperm.
PLUS either:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent. OR
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview), as detailed below:
o Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP (See Section 12.9) who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
o Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label or SmPC for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
See Section 12.8.5 for contraception requirements in the UK.
- Demonstrate adequate organ function as defined in Table 1; all screening labs should be performed within 10 days of the first dose of trial treatment.
Exclusion Criteria
Has had a prior anticancer mAb within 4 weeks prior to first dose of trial treatment or who has not recovered (ie, Grade ≤1 or at baseline) from AEs due to mAbs administered more than 4 weeks prior to first dose of trial treatment. Note: Treatment with Denosumab as standard of care for bone metastases is permitted.
Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the treatment allocation/randomization.
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to treatment allocation/randomization. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor (replacement therapy for adrenal insufficiency is permitted). Note: Treatment with palliative prednisone up to 10 mg daily or corticosteroids equivalent in the manner used to treat men with prostate cancer is permitted without Sponsor notification as long as this is a stable dose prior to study entry (must be entered into the eCRF).
If a subject has undergone major surgery, they must have recovered adequately from the toxicities and/or complications from the intervention prior to starting therapy.
Has had prior treatment with therapeutic radiopharmaceuticals for prostate cancer, such as Radium-223or Leutitium-177, within 4 weeks prior to the first dose of trial treatment.
Has a known additional malignancy that has had progression or has required active treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy.
Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease.
Has an active infection requiring systemic therapy.
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Has previously participated in any other pembrolizumab trial or received prior therapy with an anti-PD-1, anti-PD-L1, and anti-PD-L2 (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
Has known active hepatitis B virus (eg, hepatitis B surface antigen reactive) or hepatitis C virus (HCV) (eg, HCV RNA [qualitative] is detected).
Has received a live vaccine or live-attenuated vaccine within 30 days of the first dose of trial treatment. Any licensed COVID-19 vaccine (including for emergency use) in a particular country is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy. Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not allowed.
Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (eg, saw palmetto, ginkgo, turmeric, red rice yeast, citrus pectin polysaccharide, dehydroepiandrosterone) within 4 weeks prior to treatment allocation/randomization.
Has known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate in Cohorts A, B, E, F, G, H, and I provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to treatment allocation/randomization and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Note: Subjects with brain metastasis are excluded from participating in Cohort C (pembrolizumab + enzalutamide) or D (pembrolizumab + abiraterone acetate + prednisone).
Has had prior chemotherapy, targeted small molecule therapy, abiraterone acetate treatment, enzalutamide treatment, darolutamide treatment, apalutamide treatment, or other NHA treatment, or localized radiation therapy within 2 weeks prior to first dose of trial treatment or who has not recovered (ie, Grade ≤1 or at baseline) from AEs due to a previously administered agent. Note: Subjects with Grade ≤2 neuropathy or Grade ≤2 alopecia are an exception to this criterion and may qualify for the study.
Has a “superscan” bone scan. This is defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan such that the presence of additional metastases in the future could not be evaluated.
Has had prior solid organ or bone marrow transplant.
