Phase II Trial of Palbociclib and Pembrolizumab in Central Nervous System Metastases
Overview
- Phase
- Phase 2
- Intervention
- Palbociclib
- Conditions
- Metastatic Malignant Neoplasm to Brain
- Sponsor
- Massachusetts General Hospital
- Enrollment
- 45
- Locations
- 2
- Primary Endpoint
- Intracranial Clinical Benefit Rate (Cohort 1)
- Status
- Recruiting
- Last Updated
- last month
Overview
Brief Summary
This research study is studying This research study is studying the efficacy and safety of the following study drugs as a possible treatment for recurrent central nervous system (CNS) metastases:
- Palbociclib alone (Cohort 1)
- The combination of palbociclib and pembrolizumab (Cohort 2) Pfizer and Merck, pharmaceutical companies, are supporting this research study by providing the study drugs as well as funding for research activities.
Detailed Description
This is a non-randomized, parallel cohort, Phase II study. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The study will be conducted in two independent cohorts. The first cohort (Cohort 1) is comprised of participants with measurable CNS metastases from solid tumors (including patients whose primary cancers are from lung, breast or melanoma) harboring specific alterations, and participants receive the study drug palbociclib. The second cohort (Cohort 2) will evaluate the efficacy and safety of the combination of pembrolizumab and palbociclib in recurrent brain metastases from breast cancer. Palbociclib is being studied for use in the treatment of a broad range of cancers. This type of drug inhibits cell growth in the cells called cyclin-dependent kinases which promote tumor cell proliferation. The U.S. Food and Drug Administration (FDA) has not approved palbociclib for participants with central nervous system metastases, but it has been approved for other uses. Researchers hope to study the effects of pembrolizumab. The U.S. Food and Drug Administration (FDA) has approved pembrolizumab for some diseases, but not central nervous system metastases. Many cancers use specific pathways (such as PD-1/PD-L1 and CTLA-4) to evade the body's immune system. Pembrolizumab works by blocking the PD-1/PD-L1 pathways and thus releasing the brakes on the immune system so it can stop or slow cancer. In some tumor diagnoses, there may be a correlation between a specific marker (PD-L1 status) and activity of types of immunotherapies. Participants in any cohort will receive study treatment as long as they do not experience intolerable side effects and their disease does not worsen, and will be followed for 2 years after their study treatment ends.
Investigators
Priscilla Brastianos
Principal Investigator
Massachusetts General Hospital
Eligibility Criteria
Inclusion Criteria
- •Participants must have histologically or cytologically confirmed disease from any solid tumor (Cohort 1)
- •Participants must have histologically or cytologically confirmed disease from breast cancer (Cohort 2).
- •Participants must have measurable disease in the CNS, defined as at least one lesion that can be accurately measured in at least one dimension as ≥10 mm.
- •Participants must have progressive CNS lesions, as defined by one of the following:
- •Patients may have multiple progressive CNS lesions, some of which have been treated by SRS or surgery. Patients are eligible if they have one or more un-treated (by surgery or SRS) progressive lesions that is measurable.
- •Patients have measurable residual or progressive lesions after surgery.
- •Patients who have had prior WBRT and/or SRS are eligible but there needs to be unequivocal evidence of progression of at least one lesion treated by radiation (e.g. tissue diagnosis). Biopsy can be considered for definitive diagnosis.
- •Patients who have previously been treated with systemic therapy for CNS metastases are eligible.
- •Age \> 18 years. The toxicity of palbociclib in children is unknown.
- •ECOG performance status of 0, 1 or 2 (Karnofsky ≥ 60, see Appendix A).
Exclusion Criteria
- •Prior treatment with CDK4/6 inhibitor.
- •Participants who have had chemotherapy, immunotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have ≥ grade 2 adverse events due to agents administered more than 2 weeks earlier.
- •Participants who are receiving any other investigational agents.
- •Participants who are receiving other concurrent chemotherapies or immunotherapies for their cancer (except for patients who will receive letrozole, anastrozole, exemestane, tamoxifen, fulvestrant, trastuzumab, bisphosphonates, or ovarian suppression therapy)
- •Leptomeningeal involvement of cancer (Cohort 1). Leptomeningeal involvement is allowed for Cohort
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib (including abemaciclib).
- •Participants receiving any medications or substances that are moderate or strong inhibitors or inducers of CYP3A isoenzymes are ineligible. Lists including medications and substances known or with the potential to interact with the CYP3A isoenzymes are provided in Appendix C, and can also be found within section 5.
- •Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Pregnant women are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with palbociclib, breastfeeding should be discontinued if the mother is treated with palbociclib.
Arms & Interventions
Cohort 1 (Palbociclib)
This arm involves screening for eligibility, study treatment and study visits, and follow up. Cohort 1 participants will receive palbociclib daily at a pre-determined dose for 21 days (Day 1-21) per 28-day cycle. Palbociclib is taken orally. Participants may receive study drug as long as they do not meet the criteria for ending treatment (no intolerable side effects and disease is not progressing). Participants will be followed for up to 2 years after their treatment with the study drug ends. Up to 30 participants will be enrolled in Cohort 1.
Intervention: Palbociclib
Cohort 2 (Palbociclib in Combination with Pembrolizumab)
Cohort 2 involves screening for eligibility, study treatment and study visits, and follow up. Participants in Cohort 2 will receive study drugs palbociclib and pembrolizumab. Palbociclib is taken orally once per day for 21 days (Day 1-21) of each 28-day cycle. Pembrolizumab will be administered as an intravenous (IV) infusion once every 21 days. Participants may receive study drugs as long as they do not meet the criteria for ending treatment (no intolerable side effects and disease is not progressing), and will be followed for up to 2 years after they stop study treatment. Up to 15 participants will be enrolled in Cohort 2.
Intervention: Palbociclib
Cohort 2 (Palbociclib in Combination with Pembrolizumab)
Cohort 2 involves screening for eligibility, study treatment and study visits, and follow up. Participants in Cohort 2 will receive study drugs palbociclib and pembrolizumab. Palbociclib is taken orally once per day for 21 days (Day 1-21) of each 28-day cycle. Pembrolizumab will be administered as an intravenous (IV) infusion once every 21 days. Participants may receive study drugs as long as they do not meet the criteria for ending treatment (no intolerable side effects and disease is not progressing), and will be followed for up to 2 years after they stop study treatment. Up to 15 participants will be enrolled in Cohort 2.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Intracranial Clinical Benefit Rate (Cohort 1)
Time Frame: 8 weeks (Screening through 8 weeks)
Intracranial Clinical Benefit is defined by complete response (CR), partial response (PR) or stable disease (SD) in the central nervous system (CNS). The proportion of patients in Cohort 1 with response in the CNS will be presented with a two-sided, 90% confidence interval based on the method of Atkinson and Brown, which allows for the two-stage design.
Intracranial Clinical Benefit Rate (Cohort 2)
Time Frame: 8 weeks (Screening through 8 weeks)
Intracranial clinical benefit is defined by CR, PR, or SD in the CNS. The proportion of Cohort 2 participants with response in the CNS will be presented with a two-sided, 90% exact binomial confidence interval.
Secondary Outcomes
- Extracranial Overall Response Rate(8 weeks (Screening through 8 weeks))
- Intracranial disease progression rate of Cohort 1(Time from registration to the earlier of progression or death due to any cause, up to 2 years post End of Treatment (EoT) visit.)
- Extracranial disease progression rate of Cohort 1(Time from registration to the earlier of progression or death due to any cause, for up to 2 years post EoT visit.)
- Overall Survival (OS) Rate(Registration to death due to any cause, or censored at date last known alive. Patients will be followed for a maximum of 2 years after End-of-Treatment visit.)
- Incidence of Drug Related Toxicities(Day 1 of study treatment through 30 days post last dose, an average of 1.5 years.)