Background:
* Kidney cancer is the 8th most common malignancy and 12th leading cause of cancer-related death in the United States. It is estimated that there will be 79,000 new cases of kidney cancer diagnosed in 2022, resulting in 13,920 deaths. Despite a steady increase in the incidence of renal cell cancer (RCC) over the past 3 decades, there has been an improvement in observed 5-year survival rates.
* Most patients with advanced clear cell RCC are treated with immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1) and/or the CTLA4 axis and agents targeting the vascular endothelial growth factor (VEGF) pathway. There is a paucity of options for patients who have progressed on these therapies. There is currently no widely accepted standard for patients with papillary RCC, although some patients may benefit from agents such as cabozantinib or the combination of bevacizumab and erlotinib.
* Preclinical data suggest that inhibitors of CDK 4/6 might be active in kidney cancer and that these agents might act synergistically with PD-1 checkpoint inhibitors in a variety of preclinical models.
* Palbociclib is a highly selective, reversible oral inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Inhibition of CDK 4/6 blocks DNA synthesis by prohibiting the progression of the cell cycle from G1 to the S phase. Data from nonclinical studies indicate that palbociclib may have cytostatic effects on tumor cells.
* Sasanlimab is an investigational humanized immunoglobulin G4 monoclonal antibody that binds PD-1 and blocks its interaction with its ligands, programmed death-ligand 1 and 2 (PD-L1) \& (PD-L2). It presents the distinct characteristic that it can be administered subcutaneously on a monthly basis whereas approved and other available anti-PD-1/PDL1 therapies currently are administered intravenously. In animal models, it demonstrated high-affinity interaction with PD 1 and was associated with a significant delay in the growth of murine MC-38 colorectal tumors implanted in hu-PD-1 knock-in mice.
Objectives:
* Phase I: To determine recommended phase II dose (RP2D) of palbociclib in combination with sasanlimab
* Phase II: To determine the overall response rate (ORR) defined as partial response (PR) + complete response (CR) of the RP2D of the combination of palbociclib and sasanlimab in participants with advanced ccRCC (Cohorts 1a and 2a) and advanced pRCC (Cohorts 1b and 2b) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Eligibility:
* Age 18 years or older
* Participants with histologically or cytologically confirmed advanced ccRCC or pRCC
* Participants must have measurable disease per RECIST 1.1
* ECOG performance status \<= 1
* Adequate organ function as defined by the liver, kidney, and hematologic laboratory testing
* Participants with ccRCC must have received checkpoint inhibitor therapy and must have received or been ineligible to receive a VEGF pathway antagonist (as a single agent or as part of a combination)
* Participants with pRCC can be treatment-na(SqrRoot) ve or have previously received systemic treatment for pRCC.
* No more than four prior lines of therapy in the metastatic setting.
Design:
* The proposed study is an open label, phase I/II study of palbociclib in combination with sasanlimab
* Participants will be enrolled simultaneously into Cohort 1a (ccRCC) and Cohort 1b (pRCC) and start treatment in cycles consisting of 28 (+/- 5) days
* Initially, 6-18 participants from Cohort 1a and/or Cohort 1b will be enrolled into Phase I to estimate RP2D. If RP2D is estimated, we will continue enrollment as planned into Phase II, if not, we will submit amendment with updated dosing
* Following the Phase I, the first 9 participants from each pair of Cohorts (1a+2a) and (1b+2b) enrolled at the RP2D of palbociclib and sasanlimab in Phase I and Phase II will be evaluated separately for response. If among these 9 participants from pair of Cohorts (1a+2a) and (1b+2b), no more than 1 objective response defined as CR+PR is seen, then no further participants will be enrolled in Cohort 2a or 2b
