Palbociclib With Everolimus + Exemestane In BC

• ClinicalTrials.gov Identifier: NCT02871791
• Recruitment Status: Completed
• First Posted: August 18, 2016
• Results First Posted: August 29, 2022
• Last Update Posted: August 29, 2022
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Pfizer
• Information provided by (Responsible Party): Sara Tolaney, Dana-Farber Cancer Institute

Tracking Information

• First Submitted Date: June 29, 2016
• First Posted Date: August 18, 2016
• Results First Submitted Date: January 26, 2022
• Results First Posted Date: August 29, 2022
• Last Update Posted Date: August 29, 2022
• Actual Study Start Date: August 24, 2016
• Actual Primary Completion Date: December 3, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 2, 2022)

Clinical Benefit Rate (CBR) [Phase 2a] [ Time Frame: Disease evaluations were performed every 8 weeks (within 24 weeks of initiation of study treatment) or every 12 weeks (greater than 24 weeks of initiation of study treatment). Treatment duration has a median of 111 days and maximum of 681 days. ]

CBR is defined as the proportion of participants achieving complete response, partial response or stable disease for more than 6 months (CR+PR+SD ≥ 24 weeks) taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.

Original Primary Outcome Measures (submitted: August 15, 2016)

• Number of participants with Dose-Limiting Toxicities (DLT) [ Time Frame: Baseline to 28 Days (1 cycle) ]
  first cycle DLTs in order to determine maximum tolerated dose of the combination of palbociclib, everolimus and exemestane.
• Clinical Benefit Rate [ Time Frame: 2 Years ]

Current Secondary Outcome Measures (submitted: August 2, 2022)

• Overall Response Rate (ORR) [Phase 2a] [ Time Frame: Disease evaluations were performed every 8 weeks (within 24 weeks of initiation of study treatment) or every 12 weeks (greater than 24 weeks of initiation of study treatment). Treatment duration has a median of 111 days and maximum of 681 days. ]
  The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment.
• Disease Control Rate (DCR) [Phase 2a] [ Time Frame: Disease evaluations were performed every 8 weeks (within 24 weeks of initiation of study treatment) or every 12 weeks (greater than 24 weeks of initiation of study treatment). Treatment duration has a median of 111 days and maximum of 681 days. ]
  The DCR defined as the proportion of patient that has CR+PR+SD>=12 weeks. Response will be assessed among participants eligible for the phase IIa part of the study who received at least one dose of the study drugs at the MTD/RP2D and have measurable disease at screening.
• Duration of Response (DOR) [Phase 2a] [ Time Frame: Disease evaluations were performed every 8 weeks (within 24 weeks of initiation of study treatment) or every 12 weeks (greater than 24 weeks of initiation of study treatment). Treatment duration has a median of 111 days and maximum of 681 days. ]
  Response will be assessed among participants eligible for the phase IIa part of the study who received at least one dose of the study drugs at the MTD/RP2D and have measurable disease at screening. DOR defined based on the duration of stable disease.
• Median Progression Free Survival (PFS) [Phase 2a] [ Time Frame: Disease is evaluated and followed-up every 8 weeks, with median of 20.04 months and maximum of 35.64 months. ]
  Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

Original Secondary Outcome Measures (submitted: August 15, 2016)

• Overall Response Rate [ Time Frame: 2 Years ]
  Response will be assessed among participants eligible for the phase IIa part of the study who received at least one dose of the study drugs at the MTD/RP2D and have measurable disease at screening.
• Disease Control Rate [ Time Frame: 2 Years ]
  Response will be assessed among participants eligible for the phase IIa part of the study who received at least one dose of the study drugs at the MTD/RP2D and have measurable disease at screening.
• Duration of Response [ Time Frame: 2 Years ]
  Response will be assessed among participants eligible for the phase IIa part of the study who received at least one dose of the study drugs at the MTD/RP2D and have measurable disease at screening.
• Progression Free Survival [ Time Frame: 2 Years ]
  PFS will be described using the method of Kaplan-Meier, and it will be presented with a 95% confidence interval. Participants alive without disease progression are censored at the date of last disease evaluation.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Palbociclib With Everolimus + Exemestane In BC
• Official Title: A Phase 1b/2a Study Of Palbociclib In Combination With Everolimus And Exemestane In Postmenopausal Women With Estrogen Receptor Positive and HER2 Negative Metastatic Breast Cancer

Brief Summary

This research study is studying a combination of targeted therapy and hormonal therapy as a possible treatment for breast cancer that has spread to other places in the body and is hormone receptor positive (HR+) and HER2-negative.

The names of the study interventions involved in this study are:

• Palbociclib
• Everolimus
• Exemestane

Detailed Description

This is a Phase I/II clinical trial. The Phase I portion of this clinical trial tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. The Phase II portion of the study tests 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 FDA (the U.S. Food and Drug Administration) has not approved the combination of Palbociclib, Everolimus, and Exemestane as a treatment for any disease.

This is the first time that the combination of Palbociclib, Everolimus, and Exemestane will be given to humans.

Palbociclib is a drug that may stop cancer cells from growing. Palbociclib blocks activity of two closely related enzymes (proteins that help chemical reactions occur in the body), called Cyclin D Kinases 4 and 6 (CDK 4/6). These proteins are part of a pathway, or a sequence of steps, which is known to regulate cell growth. Laboratory testing has suggested Palbociclib may stop the growth of HR+ breast cancer.

Everolimus is a type of drug called an mTORinhibitor that treats breast cancer by preventing the cells from multiplying by inhibiting the pathway, or a sequence of steps, known to regulate cell reproduction. Everolimus also may stop the growth of cancer cells by decreasing blood supply to the cancer cells.

Exemestane is an anti-hormone therapy that prevents breast cancer cell growth by blocking estrogen receptor stimulation. Premenopausal women will also receive an injection drug called an LHRH (luteinizing hormone-releasing hormone) agonist to shut down ovary function. It is standard of care for people with breast cancer, specifically with HR+ breast cancer, to take anti-hormone therapy.

The combination of everolimus and exemestane is FDA approved to treat this type of breast cancer.

The purpose of the Phase I portion of this research study is to determine a safe and tolerable dose of the combination of Palbociclib, Everolimus, and Exemestane for participants with ER-positive, HER2-negative advanced breast cancer.

The purpose of the Phase II portion of this research study is to determine whether the combination of Palbociclib, Everolimus, and Exemestane is an effective treatment for participants with ER-positive, HER2-negative advanced breast cancer.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
• Hormone Receptor (HR)-Positive Breast Cancer

Intervention

• Drug: Palbociclib
• Drug: Everolimus
• Drug: Exemestane

Study Arms

Experimental: Palbociclib, Everolimus, Exemestane

• Palbociclib will be administered orally, 100mg, once daily for 21 consecutive days followed by a 7-day rest (28-day cycle)
• Everolimus will be administered orally, 5mg, once daily on a 28 day schedule
• Exemestane will be administered orally, 25mg, once daily on a 28 day schedule

Interventions:

• Drug: Palbociclib
• Drug: Everolimus
• Drug: Exemestane

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 25, 2020): 41
• Original Estimated Enrollment (submitted: August 15, 2016): 32
• Actual Study Completion Date: September 2021
• Actual Primary Completion Date: December 3, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participants must meet the following criteria on screening examination to be eligible to participate in the study. Laboratory tests required for eligibility must be completed within 14 days prior to the date of registration. Diagnostic tests, such as MRIs and CT scans, must be performed within 30 days of registration and baseline measurements must be documented within 14 days of the date of registration.
• Participants with histologically or cytologically confirmed hormone receptor (HR)-positive, Her2-negative metastatic breast cancer. Central confirmation of HR positivity is not required

• Postmenopausal women as defined as:

  • Age >60 years

    --- or

  • Age >45 with intact uterus and amenorrhea for ≥ 12 consecutive months or Follicle stimulating hormone (FSH) levels within postmenopausal range according to the ranges established by the testing facility

    --- or

  • Premenopausal women who have been on a GnRH agonist for at least 6 weeks prior to study entry. Women in this group MUST remain on the GnRH agonist for the duration of protocol treatment

    --- or

  • Status post bilateral oophorectomy, after adequate healing post surgery;
• Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.
• Participants must have measurable disease as per RECIST 1.1.

• Prior Treatment Specifics:

  • Participants must have radiological or objective evidence of progression to a CDK4/6 inhibitor regimen in the metastatic setting AND relapse/progression on an NSAI (defined as either relapsed ≤ 12 months after completing adjuvant NSAI or progressed through an NSAI for metastatic or locally advanced breast cancer)
  • Participants may have received any number of previous endocrine/hormonal lines of therapy in the metastatic setting, as long none of them were exemestane-based and the last dose is ≥ 14 days prior to registration;
  • Participants may have received up to one prior chemotherapy line for advanced breast cancer as long as the last dose is ≥ 21 days prior to registration;
  • Participants may have received prior biologic treatments or investigational drugs as long as the last dose is ≥ 21 days prior to registration;
  • Participants may have received radiotherapy for palliative purposes but must not be experiencing > grade 1 treatment related toxicities and have completed treatment ≥ 14 days prior to registration
• Age ≥18 years. Age restriction applies given that no dosing or adverse event data are currently available on the use of palbociclib or exemestane in participants <18 years of age.
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
• For participants enrolling the phase IIa part of the study, accessible tumor lesion(s) for the purpose of research biopsy and willingness to undergo a research biopsy before treatment initiation and at the time of disease progression, as well as a single research blood sample before initiation of therapy. Participants who undergo an attempted on-treatment research biopsy and in whom inadequate tissue is obtained are still eligible to receive protocol therapy. They will not be required to undergo a repeat research biopsy attempt.
• For participants enrolling the phase IIa part of the study, willingness to provide archival tumor samples when available.

• Participants must have normal organ and marrow function, as defined below:

  • absolute neutrophil count ≥1,5x109/L
  • platelets ≥100 x109/L
  • total hemoglobin ≥ 9 g/dL (which may be post transfusion)
  • total bilirubin ≤1.5 x institutional upper limit of normal
  • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal or ≤5 × institutional upper limit of normal for participants with liver metastization
  • creatinine ≤1.5 x above institutional normal or ≥ 60 ml/min/1.73m2 for subjects with creatinine levels above institutional normal.
  • baseline QTc < 500 ms
  • fasting plasma glucose <140 mg/dL / 7.8 mmol/L
• The effects of the combination of palbociclib, everolimus and exemestane on the developing human fetus are unknown. Given that women in this study will be post-menopausal by eligibility criteria (de facto or pharmacologically induced), it is expected that there will be no women of child-bearing potential in this study. If, for any reason, a woman should become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately. Of note, premenopausal women and men are only eligible if they have been on a GnRH agonist for at least 6 weeks prior to study entry. These participants MUST remain on the GnRH agonist for the duration of protocol treatment. Such participants should be counseled prior to study entry that GnRH agonists alone may not be adequate contraception and that adequate contraception (barrier method of birth control; abstinence) should be employed for the duration of study participation.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Participants who have demonstrated intolerance to 125mg of Palbociclib are ineligible for the Phase I portion.
• Participants who are receiving any other investigational agents.
• Participants who have received previous treatment with an mTOR inhibitor or exemestane.
• Participants with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib, everolimus or exemestane.
• Participants with known brain metastases may be enrolled in this study if radiation therapy and/or surgery have been completed with a minimum of 3 months of stable disease demonstrated on serial evaluation by CT (with contrast enhancement) or MRI. Such participants must no longer require treatment with corticosteroids or enzyme inducing anti-epileptic medications for their CNS disease.
• Participants with bilateral diffuse lymphangitic carcinomatosis.
• Participants with significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates.
• Evidence of current pneumonitis
• Subjects with organ allograft requiring immunosuppression.

• Participants with uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation;
  • Impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea or malabsorption syndrome).
• Participants receiving any medications or substances that are moderate or strong inhibitors or inducers of CYP3A within 7 days of registration. 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 Sections 2.4.1.2 and 5.8. 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.
• Proton pump inhibitors(PPI) may be taken while on study, however it is recommended that the PPI is taken 12 hours from the time of palbociclib administration. If needed, alternative antacid therapies may be used including H2-receptor antagonists and locally acting antacids. H2-receptor antagonists should be administered with a staggered dosing regimen (twice daily). The dosing of palbociclib should occur at least 10 hours after H2-receptor antagonist evening dose and 2 hours before the H2-receptor antagonist morning dose.
• Pregnant women are excluded.
• Individuals with a history of a different malignancy are ineligible except for the following circumstances: a) if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; b) if diagnosed with the following cancers and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
• Participants known to be HIV-positive on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with palbociclib and everolimus. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated. Screening for HIV infection at baseline is not required.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02871791
• Other Study ID Numbers: 16-177
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Sara Tolaney, Dana-Farber Cancer Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Dana-Farber Cancer Institute
• Original Study Sponsor: Same as current
• Collaborators: Pfizer

Investigators

• Principal Investigator: Sara Tolaney, MD; Dana-Farber Cancer Institute

• PRS Account: Dana-Farber Cancer Institute
• Verification Date: August 2022