Phase I/II Study of CDK4/6 Inhibition With Abemaciclib to Upregulate PSMA Expression Prior to 177Lu-PSMA-617 Treatment in Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC) Previously Treated With Novel Hormonal Agents and Chemotherapy
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Vadim S Koshkin
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Recommended phase 2 dose (Part A)
Overview
Brief Summary
This phase I/II trial tests the safety, side effects, and best dose of abemaciclib and whether it works before 177Lu-PSMA-617 in treating patients with castration resistant prostate cancer that has spread to other places in the body (metastatic). Abemaciclib is in a class of medications called kinase inhibitors. It is highly selective inhibitors of cyclin-dependent kinase 4 and 6, which are proteins involved in cell differentiation and growth. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. Radioligand therapy uses a small molecule (in this case 177Lu-PSMA-617), which carries a radioactive component to destroys tumor cells. When 177Lu-PSMA-617 is injected into the body, it attaches to the prostate-specific membrane antigen (PSMA) receptor found on tumor cells. After 177Lu-PSMA-617 attaches to the PSMA receptor, its radiation component destroys the tumor cell. Giving abemaciclib before 177Lu-PSMA-617 may help 177Lu-PSMA-617 kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose (RP2D) for abemaciclib given as lead-in treatment prior to lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) for each treatment cycle, as well as dose limiting toxicities (DLTs) of this combination regimen. (Part A)
II. To determine the change in prostate-specific membrane antigen (PSMA) uptake on gallium Ga 68 gozetotide (68Ga-PSMA-11) positron emission tomography (PET) scan following fourteen days of priming with abemaciclib treatment, relative to the pre-treatment baseline scan. (Part B (Expanded Cohort)).
SECONDARY OBJECTIVES:
I. To determine the (proportion of patients who experience >= 50% decline from baseline in serum prostate specific antigen (PSA) (PSA50) response of this combination treatment. (Part B [Expanded Cohort]) II. To describe the safety of this combination treatment regimen using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5.0. (Part B [Expanded Cohort]) III. To determine the radiographic progression free survival (rPFS) according to Prostate Cancer Working Group 3 (PCWG3) guidelines among patients treated with this combination regimen. (Part B [Expanded Cohort]) IV. To determine the objective response rate (ORR) (complete response [CR] + partial response [PR]) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 response in soft tissue, lymph node and visceral lesions. (Part B [Expanded Cohort]) V. To determine the disease control rate (DCR) (CR + PR + stable disease (SD)) as measured by RECIST v1.1 response in soft tissue, lymph node and visceral lesions. (Part B [Expanded Cohort]) VI. To determine the overall survival (OS) of patients treated with this combination regimen. (Part B [Expanded Cohort]) VII. To determine the median duration of response (DOR) in patients treated with this combination regimen who achieve CR or PR as measured by RECIST v1.1. (Part B [Expanded Cohort])
EXPLORATORY OBJECTIVES:
I. To assess changes in tumor microenvironment using ribonucleic acid (RNA) and whole exome sequencing by comparing biopsies obtained pre and post-combination treatment using the established institutional biopsy protocol (PSMA biopsy study).
II. To assess changes in PSMA expression in biopsies at the time of progression relative to pre-treatment biopsies using immunohistochemistry (IHC).
III. To describe PSMA upregulation on imaging following 7 days of treatment with abemaciclib, and in particular compare to PSMA upregulation on imaging seen following 14 days of abemaciclib treatment.
IV. To describe PSMA expression and upregulation on imaging following combined treatment with abemaciclib and 177Lu-PSMA-617 at the time of subsequent therapy cycles (pre and post abemaciclib treatment with cycle 3) in some patients treated with RP2D in Part B (expansion cohort).
V. To describe patterns of progression following completion of treatment, including in patients with available 68Ga-PSMA-11 PET scans.
VI. To compare response to treatment and clinical outcomes with different dose levels of abemaciclib used in this study.
OUTLINE: This is a dose-escalation study of abemaciclib.
Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-14 and lutetium Lu 177 vipivotide tetraxetan intravenously (IV) over 30 minutes on day 15. Treatment repeats every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study intervention, patients are followed up at 30 days, and then will subsequently be followed for overall survival in the long-term follow-up period and contacted approximately every 3 months until consent is withdrawn, death occurs, patient is lost to follow-up or the study is concluded.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participants must have histologically or cytologically confirmed prostate cancer. Either fresh biopsy or archival tissue can be used for confirmation.
- •Age \>= 18 years.
- •Patients must have metastatic castration resistant prostate cancer (mCRPC) with progression based on Prostate Cancer Working Group 3 (PCWG3) criteria.
- •Patients must have adenocarcinoma histology.
- •Prior treatment with at least one novel hormonal agents (NHA) such as abiraterone acetate, enzalutamide, apalutamide, darolutamide etc.
- •Patients must have prior orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum testosterone (\< 50 ng/dL or \< 1.7 nmol/L)
- •Patients must have a 68Ga-PSMA-11 PET scan with at least one PSMA-positive lesions (maximum standardized uptake value \[SUVmax\] greater than SUVmax of liver) as determined by nuclear medicine review prior to start of lead-in treatment with abemaciclib
- •Patients must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2
- •Patients must have life expectancy of \> 6 months
- •Patients must have adequate organ function as outlined below and bone marrow reserve
Exclusion Criteria
- •Patients with small cell or neuroendocrine carcinoma histology.
- •Patients with a super scan seen in the baseline bone scan. Super scan refers to a bone scan with diffusely increased skeletal radioisotope uptake relative to soft tissue
- •Patients with prior treatment with CDK4/6 inhibitors
- •Patients with prior treatment with PSMA-targeted radioligand therapy. Patients with previous treatment with PSMA targeting therapies (Such as Chimeric antigen receptor T cells (CAR-T) or Bi-specific T-cell engagers (BiTEs) are eligible.
- •Patients treated with Radium-223 within 6 weeks prior to study entry.
- •Any systemic anti-cancer therapy within 3 weeks of study entry
- •Patients who have experienced significant radiation-related adverse events (AEs) from prior radiation treatment (\>= grade 3) or have experienced persistent radiation-related AEs that have not resolved by the time of study randomization
- •Patients with a history of central nervous system (CNS) metastases are ineligible unless they have received prior therapy (surgery, radiation therapy (RT), gamma knife) are asymptomatic, and not receiving corticosteroids for this indication. Head imaging is not required
- •Patients with symptoms of cord compression or impending cord compression
- •Patients with concurrent serious medical conditions as determined by primary investigator
Arms & Interventions
Part B: Recommended Phase 2 dose of Abemaciclib, 177Lu-PSMA-617
Patients receive the recommended phase 2 dose of abemaciclib lead-in on days 1-14 and lutetium Lu 177 vipivotide tetraxetan IV over 30 minutes on day 15. Treatment repeats every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Abemaciclib (Drug)
Part A: Abemaciclib, 177Lu-PSMA-617
Patients receive abemaciclib lead-in on days 1-14 and lutetium Lu 177 vipivotide tetraxetan IV over 30 minutes on day 15. Treatment repeats every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Lutetium Lu 177-PSMA-617 (Drug)
Part B: Recommended Phase 2 dose of Abemaciclib, 177Lu-PSMA-617
Patients receive the recommended phase 2 dose of abemaciclib lead-in on days 1-14 and lutetium Lu 177 vipivotide tetraxetan IV over 30 minutes on day 15. Treatment repeats every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Lutetium Lu 177-PSMA-617 (Drug)
Part A: Abemaciclib, 177Lu-PSMA-617
Patients receive abemaciclib lead-in on days 1-14 and lutetium Lu 177 vipivotide tetraxetan IV over 30 minutes on day 15. Treatment repeats every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Abemaciclib (Drug)
Outcomes
Primary Outcomes
Recommended phase 2 dose (Part A)
Time Frame: 6 weeks
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)
Time Frame: 6 weeks
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)
Time Frame: Up to 24 weeks
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
Secondary Outcomes
- Proportion of participants with TRAEs (Part B)(Up to 30 days after last dose of study drug, approximately 28 weeks)
- Median duration of response (DOR) (Part B)(Up to 2 years)
- Median overall survival (OS) (Part B)(Up to 2 years)
- PSA50 response rate (Part B)(Up to 24 weeks)
- Radiographic progression free survival (Part B)(Up to 2 years)
- Objective response rate (Part B)(Up to 24 weeks)
- Disease control rate (Part B)(Up to 24 weeks)
Investigators
Vadim S Koshkin
Principal Investiator
University of California, San Francisco