Abemaciclib Before 177Lu-PSMA-617 for the Treatment of Metastatic Castrate Resistant Prostate Cancer

Recommended phase 2 dose (Part A)

If two or more patients in a cohort experience a dose-limiting toxicity (DLT), then the maximum tolerated dose (MTD)has been exceeded. The previous dose level will be considered the MTD and the recommended phase 2 dose. Per Investigator discretion, the recommended phase 2 dose/schedule of abemaciclib followed by 177Lu-PSMA-617 may be established in the absence of reaching MTD, based on the cumulative safety data of the treatment regimen.

Proportion of participants with DLTs (Part A)

Any non-hematologic, treatment-related adverse event (TRAE) Grade 3+, except of Grade 3 nausea,vomiting,diarrhea,constipation,fever,fatigue,skin rash,alopecia or non-clinically significant laboratory that resolves to Grade \<3 within 72 hours;Grade 4 thrombocytopenia lasting \>7 days;Grade 3+ thrombocytopenia with bleeding/requirement for platelet transfusion;Grade 4 neutropenia lasting \>7 days; Grade 3+ neutropenic fever;Grade 4+ anemia;TRAE requiring treatment discontinuation/delay of \>42 days;Failure to receive at least 66% of abemaciclib doses due to toxicity;Death not clearly due to underlying disease/extraneous causes;Hy's law;Grade 3+ nausea/vomiting/diarrhea \>72 hours;Grade 3+ fatigue \>7 days;Grade 3+ electrolyte abnormality \>72 hours, unless patient has clinical symptoms;All AEs of specified grades should count as DLTs except those that are clearly due to progression/extraneous causes.

Change in maximum standardized uptake value (SUVmax) across three lesions on gallium Ga 68 gozetotide (68Ga-PSMA-11) positron emission tomography (PET) scan (Part B)

The uptake in the three lesions with the highest SUVmax on the initial scan will be compared to SUVmax measurements in the same lesions on the PSMA PET scan following 14 days of priming treatment with abemaciclib

PSA50 response rate (Part B)

The proportion of patients who achieve a greater than 50% decline from baseline prostate specific antigen (PSA) drawn prior to cycle 1 day 1, at any point in the treatment course, will be descriptively reported along with 95% binomial confidence interval.

Proportion of participants with TRAEs (Part B)

Evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 CTCAE v.5) and defined as any adverse event which is classified by the investigator as having a definite, probable, or possible attribution to study treatments.

Radiographic progression free survival (Part B)

Radiographic progression of disease will be defined by RECIST version 1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. For the first scheduled reassessment by bone scan, new bone lesions will require a confirmatory bone scan 6 or more weeks later. Median progression free survival will be estimated using the Kaplan-Meier method. Durations will be measured from the first day of study treatment (cycle 1) to the first date of radiographic progression or death, whichever occurs first. Patients who discontinue study treatment for toxicity, withdraw from the study, or have PSA-only progression will be censored at the date of the last radiographic tumor assessment. Patients who discontinue treatment for clinical progression or deterioration will be included in the analysis.

Objective response rate (Part B)

Measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 response in soft tissue, lymph node and visceral lesions. Objective response is defined as the best response (complete response or partial response) from the start of treatment until disease progression or recurrence, where the reference for progressive disease is the smallest measurements recorded from start of treatment. To be assigned a status of objective response (CR or PR), changes in tumor measurements must be confirmed by repeat scans no less than 4 weeks after the criteria for response are first met. The proportion of patients with objective response will be descriptively reported with 95% binomial confidence interval.