Neo-DAB: Darolutamide and Abemaciclib in Prostate Cancer

Recruitment & Eligibility

Status: Active, not recruiting

Sex: Male

Target Recruitment: 9

Inclusion Criteria

Inclusion Criteria For Phase 1: - Provision of signed informed consent prior to any study specific procedures, or have a legally authorized representative sign on the participant's behalf. - Ability to swallow oral medications and comply with study procedures and requirements. - Males =18 years - Histologically or cytologically confirmed adenocarcinoma of the prostate without histologic variants (including neuroendocrine differentiation, small cell, sarcomatoid, ductal adenocarcinoma, squamous or transitional cell carcinoma) comprising >50% of the sample as determined by academic medical center pathology review; men without histologic confirmation are eligible provided there is unequivocal evidence of prostate cancer (eg. very high PSA) in the view of the treating physician. - M0 or M1 (by CT/MRI and bone scans) CRPC with evidence of progression at study entry demonstrated during continuous androgen deprivation therapy (LHRH/GnRH agonists/antagonists/post orchiectomy) and castrate level of serum testosterone (=50 ng/dl). Progression is defined as one or more of the following: - Sequence of at least 2 rising PSA values at a minimum of 1-week intervals with the last result being at least 1.0 ng/mL if confirmed PSA rise is the only indication of progression. Patients who received an anti-androgen (flutamide, bicalutamide or nilutamide) must have PSA progression =4 weeks after the last dose. - Radiographic progression per RECIST 1.1 for soft tissue and/or per PCWG3 for bone (i.e., appearance of =2 new bone lesions), with or without PSA progression. - Serum testosterone level must be =50 ng/dL (1.73 nmol/L) at the screening visit. Participants who have not undergone bilateral orchiectomy are required to continue LHRH/GnRH agonists/antagonists) throughout the study. - ECOG performance status =2 (Karnofsky =60%, see Appendix A). - Participants must have adequate organ and marrow function as below: - System Laboratory Value - Hematologic - ANC =1.5×109/L - Platelets =100×109/L - Hemoglobin =9g/dL (=90g/L) independent of transfusions - Hepatic - Total Bilirubin =1.5 × ULN OR <2 × ULN if known or suspected Gilbert's syndrome - ALT and AST =3 × ULN OR =5 × ULN if liver metastases present - Renal - eGFR =30 mL/min/1.73 m2 (based on Cockcroft-Gault formula [Appendix D] OR 24 hour urine collection. - Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ANC = absolute neutrophil count; eGFR = estimated glomerular filtration rate; ULN = upper limit of normal. - The effects of darolutamide and abemaciclib on the developing human fetus are unknown. Participants and their partners must agree to use an effective contraception method (hormonal or barrier method of birth control, or abstinence) during the study and for 3 weeks after the last dose of study treatment (darolutamide and/or abemaciclib) if engaged in sex with a woman of childbearing potential, and participants must not donate sperm during this period. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. Inclusion Criteria for Phase 2: - Provision of signed informed consent prior to any study specific procedures, or have a legally authorized representative sign on the participant's behalf. - Ability to swallow oral medications and comply with study procedures and requirements. - Males =18 years. - Histologically confirmed adenocarcinoma of the prostate without histologic variants (including neuroendocrine differentiation, small cell, sarcomatoid, ductal adenocarcinoma, squamous or transitional cell carcinoma) comprising >50% of the sample as determined by academic medical center pathology review. - =3 biopsy cores (either systematic or targeted, or a combination) involved with prostate cancer. Prostate biopsy must have been performed within 6 months of screening. <3 biopsy cores with cancer are allowed if the patient has >1cm of tumor or =cT3 disease on MRI prostate. - Participants must have at least 1 biopsy core with either: - Gleason =8 OR - Gleason 4+3=7 AND at least one of the following: - PSA >20ng/dL - =cT3 disease by MRI - Evidence of EPE on biopsy - No evidence of metastatic disease as determined by radionuclide bone scan and CT/MRI, and/or PSMA-PET. Pelvic lymph nodes <2cm in short axis are permitted. If PSMA-PET does not show evidence of metastatic disease, CT/MRI and bone scan is not required. Either PSMA-PET or CT/MRI abdomen and bone scan is required before C1D1. NOTE: participants with possible evidence of bone, nodal or visceral metastatic disease on PSMA-PET imaging at baseline (but not CT/MRI or bone scan) are eligible and their participation is encouraged. All participants treated at DFCI must undergo PSMA-PET at baseline or within 28 days of C1D1 (per institutional practice) and will also undergo a research-only PSMA-PET after completion of therapy and prior to RP. - Participants must be candidates for RP and be considered surgically resectable by a Urologist. - ECOG performance status =1 (Karnofsky =70%, see Appendix A). - Participants must have adequate organ and marrow function as defined below: - System Laboratory Value - Hematologic - ANC =1.5×109/L - Platelets =100×109/L - Hemoglobin=9g/dL (=90g/L) independent of transfusions - Hepatic - Total Bilirubin =1.5 × ULN, <2 × ULN if known or suspected Gilbert's syndrome - ALT and AST =3 × ULN - Renal - eGFR =30 mL/min/1.73 m2 (based on Cockcroft-Gault formula [Appendix D] OR 24 hour urine collection. - Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ANC = absolute neutrophil count; eGFR = estimated glomerular filtration rate; ULN = upper limit of normal. - The effects of darolutamide and abemaciclib on the developing human fetus are unknown. Participants and their partners must agree to use an effective contraception method (hormonal or barrier method of birth control, or abstinence) during the study and for 3 weeks after the last dose of study treatment (darolutamide and/or abemaciclib) if engaged in sex with a woman of childbearing potential, and participants must not donate sperm during this period. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. Exclusion Criteria for Phase 1: - Participants who have had chemotherapy or radiotherapy within 4 weeks prior to planned cycle 1 day 1 of study treatment. - Participants who have received anti-neoplastic intervention or experimental antineoplastic therapy within 14 days of planned cycle

Exclusion Criteria

Not provided

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Phase 1 - Maximum Tolerated Dose (MTD);Phase 1 - Dose Limiting Toxicity (DLT);Phase 1 - Recommended Phase 2 Dose (RP2D);Phase 2 - Pathological Response Rate

Secondary Outcome Measures

Name	Time	Method
Phase 1 - Objective Response Rate (ORR);Phase 1 - Median Radiographic Progression-Free Survival (rPFS);Phase 1 & 2 - Grade 3 or Higher Treatment-Related Toxicity Rate;Phase 2 - Frequency of Certain Adverse Event (AE);Phase 2 - Change in Prostate Specific Antigen (PSA);Phase 2 - 3-year biochemical progression-free survival (bPFS) Rate;Phase 2 - 5-year progression-free survival (bPFS) Rate;Phase 2 - Proportion free from Prostate Cancer Therapy

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