This research study is trying to determine the safety and efficacy of the combination of two oral drugs, abemaciclib and darolutamide, with androgen deprivation therapy (ADT) in the treatment of metastatic, non-metastatic, and advanced prostate cancers. The first phase of the study is to establish a recommended dose for the second phase. The names of the study drugs and interventions involved in this study are: * Darolutamide * Abemaciclib * Androgen deprivation therapy (ADT) - this includes several different treatments, including Gonadotropin-Releasing Hormone (GnRH) antagonists and agonists It is expected that about 93 people will take part in the research study. Treatment is expected to last 6 months with a follow up period of up to 4.5 years.
This research study is a Phase I/II clinical trial to determine the safety and efficacy of the combination of abemaciclib and darolutamide with androgen deprivation therapy (ADT) in the treatment of metastatic and non-metastatic castration-resistance prostate cancer (CRPC) and for participants with high-risk, localized prostate cancer who will be undergoing radical prostatectomy (RP). A Phase I/II clinical trial tests the safety of investigational drugs with a lead-in phase and attempts to define the maximum tolerated dose of the investigational drugs to use for the second phase. "Investigational" means that the drugs are being studied together for the first time. The names of the study drugs and interventions involved in this study are: * Darolutamide * Abemaciclib * Androgen deprivation therapy (ADT) - this includes several different treatments, including Gonadotropin-Releasing Hormone (GnRH) agonists, Leuprolide and Goserelin, and GnRH antagonist, Degarelix In Phase I, participants will receive abemaciclib in combination with darolutamide and ADT at different dosages. In Phase II, participants will be randomized into two groups of treatment: abemaciclib, darolutamide, and ADT versus darolutamide and ADT. Randomization means that participants are placed into one of the treatment groups by chance, like flipping a coin. The U.S Food and Drug Administration (FDA) has approved androgen deprivation therapy as a treatment for prostate cancer. The FDA has not approved abemaciclib for prostate cancer but it has been approved for other uses. Abemaciclib is approved for use in advanced breast cancer. The FDA has approved darolutamide as a treatment option in men with non-metastatic CRPC but it is not approved in men with metastatic CRPC or localized prostate cancer. Research procedures include screening for eligibility, study treatment including evaluations, blood collection, and radiology scans of the prostate. It is expected about 93 participants will take part in this research study. Treatment is expected to last 6 months with a follow up period of up to 4.5 years. Lilly is supporting this research study by providing funding and the study drug, abemaciclib. Bayer is supporting the study by providing the study drug, darolutamide. The trial was intended to be Phase 1/2 but did not move forward to Phase 2 since the company providing drug and funding (Lilly) withdrew support for the trial based on data relating to abemaciclib in advanced prostate cancer.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
9
Tablet administered orally, per protocol, 2 x daily. Darolutamide is an orally administered molecular drug therapy that blocks the action of testosterone, the male sex hormone which can stimulate growth of prostate cancer.
Tablet administered orally, per protocol, 2 x daily. Abemaciclib is an orally administered molecular drug therapy that is called a "CDK4/6 inhibitor". CDK4 and CDK6 are enzymes that are involved in helping healthy and cancerous cells divide and blocking these enzymes can stop cancerous cells from growing.
Administered via intramuscular injection, per standard of care. GnRH agonist is a hormonal therapy drug.
Administered via subcutaneous injection, per standard of care. GnRH agonist is a hormonal therapy drug.
Administered via subcutaneous injection, per standard of care. GnRH antagonist is a hormonal therapy drug.
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Phase 1 - Maximum Tolerated Dose (MTD)
The Maximum Tolerated Dose (MTD) for the study drug combination is defined as the maximum dose combination at which \<33% of patients experience a Dose limiting toxicity (DLT) during Cycle 1 (the DLT-evaluation period). If a DLT is observed in 1 of 3 patients, then 3 additional patients will be enrolled at that same dose level. Dose escalation will continue to a dose of abemaciclib 200mg bid, which is the maximal dose levels. If DLTs are seen in 0-1 of 6 patients at dose level +1 (darolutamide 600mg bid and abemaciclib 200mg bid), then this will be the RP2D; otherwise the maximally tolerated dose (MTD) will be the RP2D.
Time frame: 28 days/Cycle 1, up to 6 months
Phase 1 - Dose Limiting Toxicity (DLT)
Dose Limiting Toxicity (DLT) for Phase 1 is defined as an adverse event that is related to Darolutamide and Abemaciclib with an attribution of possible, probable or definite and occurs during and/or begins during the first 28 days of the study treatment, using NCI CTCAE criteria version 5.0.
Time frame: 28 days/Cycle 1, up to 6 months
Phase 1 - Recommended Phase 2 Dose (RP2D)
RP2D will be determined after an Maximum Tolerated Dose (MTD) is identified or the maximum planned dose is achieved. Recommended Phase 2 Dose (RP2D) is defined as no more than 0-1 patients with dose limiting toxicity out of 6 at maximal dose level. Otherwise, the maximally tolerated dose will be used.
Time frame: 28 days/Cycle 1, up to 6 months
Phase 2 - Pathological Response Rate
Pathologic response is defined as achieving either a complete response (pCR) or minimal residual disease (MRD, defined as ≤5mm residual tumor) at Radical Prostatectomy (RP) in both arms
Time frame: Disease evaluated from baseline to Pre-Radical Prostatectomy (RP), up to 6 months
Phase 1 - Objective Response Rate (ORR)
The objective response rate (ORR) is defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Disease evaluated every 12 weeks, up to 6 months
Phase 1 - Median Radiographic Progression-Free Survival (rPFS)
Radiographic Progression-Free Survival (rPFS) is defined as the time from protocol treatment initiation to the earlier of progression by PCWG3 criteria73 or death due to any cause. PCWG3 progression is defined as when it is felt by the treating physician that the patient is "no longer clinically benefiting" (NLCB) from therapy. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time frame: Evaluated every 12 weeks, up to 6 months
Phase 1 & 2 - Grade 3 or Higher Treatment-Related Toxicity Rate
Defined as all grade 3 or higher adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv5 as reported on case report forms were counted. Rate is the proportion of treated participants experiencing at least one treatment-related grade 3 or higher AE of any type during the time of observation.
Time frame: 28 days, up to 6 months
Phase 2 - Frequency of Certain Adverse Event (AE)
Certain Adverse Event (AE) includes frequency of positive surgical margins, extracapsular extension, seminal vesicle invasion and lymph node positivity.
Time frame: 28 days, up to 6 months
Phase 2 - Change in Prostate Specific Antigen (PSA)
A prostate-specific antigen (PSA) test is a blood test that measures the level of PSA in a sample of blood. PSA test will be done by local institutional labs and reported as nanograms of PSA per milliliter (ng/mL) of blood
Time frame: PSA is measured day 1 of each cycle, up to 6 months. Each cycle is 28 days.
Phase 2 - 3-year biochemical progression-free survival (bPFS) Rate
3-year bPFS rate is the proportion of participants remaining alive and free of biochemical progression at 3 years. Biochemical progression is defined as a PSA rising to \>0.1ng/mL after surgery.
Time frame: at 3 years
Phase 2 - 5-year progression-free survival (bPFS) Rate
5-year bPFS rate is the proportion of participants remaining alive and free of biochemical progression at 5 years. Biochemical progression is defined as a PSA rising to \>0.1ng/mL after surgery.
Time frame: at 5 years
Phase 2 - Proportion free from Prostate Cancer Therapy
Proportion free from further prostate cancer therapy will be estimated from the Kaplan Meier methodology by each arm. Further prostate cancer therapy includes salvage radiotherapy and/or ADT.
Time frame: at 2, 3, and 5 years.
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