Palbociclib After CDK and Endocrine Therapy (PACE): A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for Endocrine Pre-treated ER+/HER2- Metastatic Breast Cancer
Overview
- Phase
- Phase 2
- Intervention
- Fulvestrant
- Conditions
- Metastatic Breast Cancer
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 220
- Locations
- 22
- Primary Endpoint
- Progression-Free Survival (PFS), According to RECIST v1.1 Criteria (Investigator Assessment)
- Status
- Active, not recruiting
- Last Updated
- 8 months ago
Overview
Brief Summary
This research study is studying three combinations of drugs as treatments for breast cancer.
The drugs involved in this study are:
- Fulvestrant
- Fulvestrant with Palbociclib
- Fulvestrant with Palbociclib and Avelumab
Detailed Description
This research study is a Phase II clinical trial. 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 and the researchers are trying to find out more about it- for example, the side effects it may cause, and the activity of a drug, or combination of drugs, against a cancer. In this research study, the investigators are evaluating the activity of fulvestrant alone, fulvestrant and palbociclib, or fulvestrant, palbociclib, and avelumab combined, in participants with metastatic hormone receptor positive HER2 negative breast cancer that has previously stopped responding to prior palbociclib and endocrine therapy. The FDA (the U.S. Food and Drug Administration) has approved both palbociclib and fulvestrant as treatment options for this disease, however the use of palbociclib has not been studied in people who have previously been treated with palbociclib. The FDA has not approved avelumab as a treatment for any disease. Palbociclib is a drug that may stop cancer cells from growing. Palbociclib blocks activity of two closely related enzymes (proteins that help chemical reactions in the body occur), called Cyclin Dependent Kinases 4 and 6 (CDK 4/6). These proteins are part of a pathway, or a sequence of steps, which is known to promote cancer cell growth. Laboratory testing has shown that palbociclib may stop the growth of hormone receptor positive breast cancer. Palbociclib is FDA-approved as therapy for metastatic hormone receptor positive HER2 negative breast cancer in combination with endocrine therapy in the first line setting, and in combination with fulvestrant for pre-treated disease. It is not known whether cancers that have grown despite prior palbociclib treatment are still sensitive to palbociclib. Endocrine therapy prevents growth of hormone receptor positive breast cancer by blocking stimulation of cancer cells by estrogen. During this study, the endocrine therapy will be fulvestrant. Fulvestrant is a drug that is approved by the FDA for treatment of metastatic hormone receptor positive breast cancer. The immune system is the body's natural defense against disease. The immune system sends a type of cells called T cells throughout the body to detect and fight infections and diseases-including cancers. One way the immune system controls the activity of T cells is through the PD-1 (programmed cell death protein-1) pathway. However, some cancer cells hide from T-cell attack by taking control of the PD-1 pathway and this stops T cells from attacking cancer cells. Avelumab is an antibody designed to block the PD-1 pathway and helps the immune system in detecting and fighting cancer cells. An antibody is a protein produced by the body's immune system when it detects harmful substances. Previous studies show that the administration of antibodies which block the PD-1 pathway can lead to tumor destruction. In the laboratory, adding avelumab to fulvestrant and palbociclib appears to improve effectiveness. It is not known whether this is true in humans
Investigators
Erica Mayer, MD, MPH
Senior Physician, Susan F Smith Center for Women's Cancers
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Participants must have histologically confirmed hormone receptor positive (HR+) HER2 negative metastatic or locally recurrent unresectable invasive breast cancer. ER, PR and HER2 measurements should be performed according to institutional guidelines, in a CLIA-approved setting. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines.
- •Men and pre- and postmenopausal women are eligible. Ongoing monthly GNRH agonist is required in pre-menopausal women or male participants for at least 4 weeks prior to study entry.
- •Participants must have radiological or objective evidence of progression on an endocrine and CDK 4/6 inhibitor regimen in the metastatic setting, and/or relapse/progression during or within 12 months of completion of an endocrine and CDK4/6 inhibitor regimen in the adjuvant setting.
- •Participants must have previously been exposed to CDK4/6 inhibitor therapy in combination with endocrine therapy. Exposure to any prior CDK4/6 inhibitor, (including palbociclib, abemaciclib, and ribociclib) is allowed. Patients may have a line of endocrine therapy after combination endocrine and CDK4/6 inhibitor exposure.
- •Participants must have remained on prior endocrine and CDK4/6 therapy in the metastatic setting without progression for at least 6 months prior to study entry.
- •It is not mandatory to have a CDK 4/6 inhibitor containing regimen as the most recent treatment.
- •Participants may have 0-1 prior lines of cytotoxic chemotherapy in the metastatic setting.
- •Prior endocrine therapy in the metastatic setting may include any aromatase inhibitor (AI) or tamoxifen, but may not include prior fulvestrant. In the metastatic setting, 1-2 prior lines of endocrine therapy are allowed.
- •Participants may have received radiotherapy for palliative purpose, but must not be experiencing \> grade 1 treatment related toxicities, and must have completed treatment \> 14 days prior to registration.
- •Age ≥18 years. Because no dosing or adverse event data are currently available on the use of study agents in participants \<18 years of age, children are excluded from this study.
Exclusion Criteria
- •Participants who have had endocrine, chemotherapy, and/or biologic therapy within 14 days prior to entering the study or those who have not recovered from any prior treatment-related toxicities (must recover to no more than grade
- •Alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 toxicity not constituting a safety risk based on investigator's judgment are acceptable).
- •Participants who are receiving concurrent therapy with other investigational agents.
- •Rapidly progressive, symptomatic, visceral spread of disease placing participant at risk of life-threatening complications in the short term.
- •Participants with active brain metastases. Stable treated brain metastases are allowed (this includes participants who have documented radiologic stability at least 4 weeks after radiotherapy, and do not require systemic steroids for management of symptoms from CNS metastatic lesions).
- •Participants who have discontinued prior palbociclib for toxicity, or have needed more than one dose or schedule reduction for toxicity from prior palbociclib therapy. If a participant required a single dose reduction during prior palbociclib therapy and tolerated it well, for example prior dosing at 100 mg qd 3 weeks on 1 week off schedule, than that dose may be selected for this trial.
- •History of allergic reactions to palbociclib or attributed to compounds of similar chemical or biologic composition to palbociclib.
- •Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)
- •Participants receiving any medications or substances that are 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 B, 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 participant 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 participant is considering a new over-the-counter medicine or herbal product.
Arms & Interventions
Fulvestrant
-Fulvestrant will be administered in the clinic as two IM injections on Cycle 1 Days 1, 15, then monthly
Intervention: Fulvestrant
Fulvestrant with Palbociclib
* Palbociclib should be taken orally, once per day for 21 days on a 28 days cyclye * Fulvestrant will be administered in the clinic as two IM injections on Cycle 1 Days 1, 15, then monthly
Intervention: Palbociclib
Fulvestrant with Palbociclib
* Palbociclib should be taken orally, once per day for 21 days on a 28 days cyclye * Fulvestrant will be administered in the clinic as two IM injections on Cycle 1 Days 1, 15, then monthly
Intervention: Fulvestrant
Fulvestrant with Palbociclib and Avelumab
* Palbociclib should be taken orally, once per day for 21 days on a 28 days cyclye * Fulvestrant will be administered in the clinic as two IM injections on Cycle 1 Days 1, 15, then monthly * Avelumab will be administered intravebously once every 2 weeks
Intervention: Palbociclib
Fulvestrant with Palbociclib and Avelumab
* Palbociclib should be taken orally, once per day for 21 days on a 28 days cyclye * Fulvestrant will be administered in the clinic as two IM injections on Cycle 1 Days 1, 15, then monthly * Avelumab will be administered intravebously once every 2 weeks
Intervention: Fulvestrant
Fulvestrant with Palbociclib and Avelumab
* Palbociclib should be taken orally, once per day for 21 days on a 28 days cyclye * Fulvestrant will be administered in the clinic as two IM injections on Cycle 1 Days 1, 15, then monthly * Avelumab will be administered intravebously once every 2 weeks
Intervention: Avelumab
Outcomes
Primary Outcomes
Progression-Free Survival (PFS), According to RECIST v1.1 Criteria (Investigator Assessment)
Time Frame: Tumor were assessed every 8 weeks until 24 weeks, then every 12 weeks. The median PFS follow-up time at database lock was 12.1 months (range 1 day to 50.1 months).
Progression-Free Survival (PFS), according to RECIST v1.1 criteria (investigator assessment): the time from randomization to the earlier of progression or death due to any cause. Participants alive without disease progression were censored at date of last disease assessment (tumor assessments). The date of progression was the first date that recurrent or progressive disease was objectively documented; if death was the defining event, it must have happened within 2 intervals of the last disease assessment, otherwise PFS was censored at last disease assessment. The length of PFS was calculated as PFS time (months) =\[progression/death date(censor date) - randomization date + 1\]/30.4375.
Secondary Outcomes
- Overall Response Rate, According to RECIST v1.1 Criteria (Investigator Assessment)(Tumor were assessed every 8 weeks until 24 weeks, then every 12 weeks. The median follow-up time for overall response rate at database lock was 12.1 months (range 1 day to 50.1 months).)
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability)(The median follow-up time for adverse event was 5.4 months (range 1.6 months to 51.2 months).)