Neo-DAB: Darolutamide and Abemaciclib in Prostate Cancer

NCT05617885 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 22-422
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Prostate Cancer; Non-metastatic Prostate Cancer; Prostate Cancer

Keywords

Prostate Cancer; Hormone Therapy; Androgen Deprivation Therapy; Metastatic Prostate Cancer; Non-metastatic Prostate Cancer; Radical Prostatectomy

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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.

  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

  Disease evaluated from baseline to Pre-Radical Prostatectomy (RP), up to 6 months

Secondary Outcomes (8)

• Phase 1 - Objective Response Rate (ORR)

  Disease evaluated every 12 weeks, up to 6 months

• Phase 1 - Median Radiographic Progression-Free Survival (rPFS)

  Evaluated every 12 weeks, up to 6 months

• Phase 1 & 2 - Grade 3 or Higher Treatment-Related Toxicity Rate

  28 days, up to 6 months

• Phase 2 - Frequency of Certain Adverse Event (AE)

  28 days, up to 6 months

• Phase 2 - Change in Prostate Specific Antigen (PSA)

  PSA is measured day 1 of each cycle, up to 6 months. Each cycle is 28 days.

Study Arms (3)

Phase 1 Lead In in CRPC

EXPERIMENTAL

Standard 3+3 dose escalation scheme with 3 dose levels of abemaciclib and a constant dose of darolutamide, per protocol, for 6, 28-day cycles

Drug: Darolutamide; Drug: Abemaciclib; Drug: GNRH-A Leuprolide Acetate; Drug: GNRH-A Goserelin; Drug: Degarelix

Phase 2 - Neoadjuvant Darolutamide and ADT prior to Radical Prostatectomy

EXPERIMENTAL

per protocol, for 6, 28-day cycles

Drug: Darolutamide; Drug: GNRH-A Leuprolide Acetate; Drug: GNRH-A Goserelin; Drug: Degarelix

Phase 2 - Neoadjuvant Darolutamide, Ademaciclib, and ADT prior to Radical Prostatectomy

EXPERIMENTAL

per protocol, for 6, 28-day cycles

Drug: Darolutamide; Drug: Abemaciclib; Drug: GNRH-A Leuprolide Acetate; Drug: GNRH-A Goserelin; Drug: Degarelix

Interventions

GNRH-A Leuprolide Acetate DRUG

Administered via intramuscular injection, per standard of care. GnRH agonist is a hormonal therapy drug.

Also known as: Eligard, Lupron Depot, Lupron Depot-Ped

Phase 1 Lead In in CRPC; Phase 2 - Neoadjuvant Darolutamide and ADT prior to Radical Prostatectomy; Phase 2 - Neoadjuvant Darolutamide, Ademaciclib, and ADT prior to Radical Prostatectomy

GNRH-A Goserelin DRUG

Administered via subcutaneous injection, per standard of care. GnRH agonist is a hormonal therapy drug.

Also known as: Zoladex

Phase 1 Lead In in CRPC; Phase 2 - Neoadjuvant Darolutamide and ADT prior to Radical Prostatectomy; Phase 2 - Neoadjuvant Darolutamide, Ademaciclib, and ADT prior to Radical Prostatectomy

Degarelix DRUG

Administered via subcutaneous injection, per standard of care. GnRH antagonist is a hormonal therapy drug.

Also known as: Firmagon

Phase 1 Lead In in CRPC; Phase 2 - Neoadjuvant Darolutamide and ADT prior to Radical Prostatectomy; Phase 2 - Neoadjuvant Darolutamide, Ademaciclib, and ADT prior to Radical Prostatectomy

Darolutamide DRUG

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.

Also known as: Nubeqa

Phase 1 Lead In in CRPC; Phase 2 - Neoadjuvant Darolutamide and ADT prior to Radical Prostatectomy; Phase 2 - Neoadjuvant Darolutamide, Ademaciclib, and ADT prior to Radical Prostatectomy

Abemaciclib DRUG

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.

Also known as: Verzenio

Phase 1 Lead In in CRPC; Phase 2 - Neoadjuvant Darolutamide, Ademaciclib, and ADT prior to Radical Prostatectomy

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 1 day 1 of study therapy.
• Participants who are receiving any other investigational agents.
• Participants who have previously received darolutamide, abemaciclib or another CDK4/6 inhibitor.
• Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e. have residual toxicities ≥Grade 2) with the exception of alopecia.
• Any of the following within 6 months before planned cycle 1 day 1 of study therapy:
• Stroke
• Myocardial infarction
• Severe/unstable angina pectoris
• Coronary/peripheral artery bypass graft
• Congestive heart failure New York Heart Association (NYHA) Class III or IV.
• Known or suspected contraindications, hypersensitivity or allergy to darolutamide or abemaciclib or to any of their excipients.
• Participants with hepatitis C, hepatitis B or human immunodeficiency (HIV) who are on anti-viral therapy that has the potential to interact with darolutamide or abemaciclib.
• Participants with untreated brain metastases. Participants with treated brain metastases are eligible if follow-up brain imaging at least 4 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression and ongoing corticosteroids are not required. Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
• Participants treated with drugs known to be strong inhibitors and/or inducers of cytochrome P450 3A4 (CYP3A4) and the treatment cannot be discontinued or switched to a different medication at least 5 half-lives prior to starting study drug.

Sponsors & Collaborators

• Praful Ravi, MB BCHir, MRCP: lead
• Eli Lilly and Company: collaborator
• Bayer: collaborator

Study Sites (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

darolutamide; abemaciclib; Leuprolide; luprolide acetate gel depot; Goserelin; acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Praful Ravi, MB BChir, MRCP

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 8, 2022
• First Posted: November 16, 2022
• Study Start: August 9, 2023
• Primary Completion: July 15, 2025
• Study Completion (Estimated): June 1, 2026
• Last Updated: February 27, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (1)