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Palbociclib

Sasanlimab and deescalating doses of palbociclib

Sasanlimab and palbociclib at the dose determined in Phase I (RP2D)

Sasanlimab will be given (SC on day 1 of every cycle, starting on day 1 (+/- 5 days) of cycle 2).

Sasanlimab

Palbociclib will be given PO for 21 days of every 28-day cycle, starting on day 1 of cycle 1.

Palbocicilib

Wanda Bell-Farrell

Ramaprasad Srinivasan, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Kidney cancer is the 12th leading cause of cancer-related death in the United States. Some kidney tumors do not respond well to current treatments. Better treatments are needed.

Objective:

To test a pair of drugs (sasanlimab and palbociclib) in people with kidney cancers.

Eligibility:

People aged 18 years and older with kidney cancer; specifically, clear cell renal cell carcinoma (ccRCC) or papillary renal cell carcinoma (pRCC).

Design:

Participants will be screened. They will have a physical exam with blood tests. They will have an imaging scan and a test of their heart function. They may have a biopsy; that is, a sample of tissue will be cut from the tumor.

Participants will be treated in 28-day cycles for up to 2 years.

Palbociclib is a pill taken by mouth. Participants will take this drug once a day for 21 days during each 28-day treatment cycle. They will write down the dates and times they take these pills in a diary.

Sasanlimab is an injection under the skin. Participants will receive this injection on the first day of each treatment cycle.

Imaging scans and blood tests will be repeated throughout the treatment. Tumor biopsies may be repeated up to 3 times; these biopsies are optional.

Participants will have follow-up visits every month for 3 months after treatment ends. They will continue to have imaging scans every 3 months; these scans may be done close to home. The results can be sent to researchers.

Participants will remain in the study up to 6 years.

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 two 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

Palbociclib and Sasanlimab for the Treatment of Advanced Clear Cell Renal Cell Carcinoma (ccRCC) or Papillary Renal Cell Carcinoma (pRCC)

A Phase I/II Study of Palbociclib and Sasanlimab for the Treatment of Advanced Clear Cell Renal Cell Carcinoma (ccRCC) or Papillary Renal Cell Carcinoma (pRCC)

.All large scale genomic sequencing data will be shared with subscribers to dbGaP. All collected IPD will be shared with other investigators after publication in accordance with the executed CRADA.

Responses (PR+CR) in participants based on imaging \[CT scan of chest, abdomen, and pelvis (or MRI of abdomen and pelvis with CT chest without contrast when appropriate)\] performed every 8 (+/-1) weeks for 32 weeks and every 12 (+/-1) weeks after that until the first of either disease progression or 6 years after enrollment

DCR as assessed by imaging \[CT scan of chest, abdomen, and pelvis (or MRI of abdomen and pelvis with CT chest without contrast when appropriate)\] performed every 8 (+/-1) weeks for 32 weeks and every 12 (+/-1) weeks after that until the first of either disease progression or 6 years after enrollment

Progression free survival determined by imaging \[CT scan of chest, abdomen, and pelvis (or MRI of abdomen and pelvis with CT chest without contrast when appropriate)\] performed every 8 (+/-1) weeks for 32 weeks and every 12 (+/-1) weeks after that until the first of either disease progression or 6 years after enrollment

Any toxicities identified between Day 1 of Cycle 1 through 90 days after the study agent (s) was/were last administered will be collected and reported by type and grade. Beyond 90 days after the last intervention, only adverse events which are serious and related to the study intervention will be recorded and reported. Note: during re-treatment AEs will be documented from the re-start of the study intervention through 90 days after the study agent (s) was/were last administered. Beyond 90 days after the last intervention, only adverse events which are serious and related to the study intervention need to be recorded

Participants assessed at Day 1 of every cycle, safety follow up visits at days 30, 60, 90, every 12 weeks until progression and/or every 6 months after progression for 6 years after enrollment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Palbociclib and Sasanlimab for the Treatment of Advanced Clear Cell Renal Cell Carcinoma (ccRCC) or Papillary Renal Cell Carcinoma (pRCC)	NCT05665361	Advanced Clear ... Papillary Renal...	Sasanlimab Palbocicilib	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Palbociclib and Sasanlimab for the Treatment of Advanced Clear Cell Renal Cell Carcinoma (ccRCC) or Papillary Renal Cell Carcinoma (pRCC)	NCT05665361	Advanced Clear ... Papillary Renal...	Sasanlimab Palbocicilib	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)

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