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Human Epidermal Growth Factor 2 Negative Carcinoma of BreastPhase 1/2NCT02871791

Palbociclib With Everolimus + Exemestane In BC

A Phase 1/2 study testing Palbociclib, Everolimus and Exemestane in people with Human Epidermal Growth Factor 2 Negative Carcinoma of Breast and Hormone Receptor (HR)-Positive Breast Cancer, run by Dana-Farber Cancer Institute at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Palbociclib, Everolimus and Exemestane
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
41 participants
Where
1 siteUnited States
Study dates
24 Aug 2016to Sep 2021
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • --- 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

Other trials in United States

About this study

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

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
Read the 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.

Being tested
Palbociclib, Everolimus, Exemestane
Keywords
Her2-negative metastatic breast cancer, Hormone receptor (HR)-positive breast cancer

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT02871791
Study groupRoleWhat they receive
Palbociclib, Everolimus, ExemestaneExperimental* 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
Receives: Drug: Palbociclib; Drug: Everolimus; Drug: Exemestane

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clinical Benefit Rate (CBR) [Phase 2a]

    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.

    Measured: 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.

Secondary outcomes (4)

  1. Overall Response Rate (ORR) [Phase 2a]

    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.

    Measured: 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.

  2. Disease Control Rate (DCR) [Phase 2a]

    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.

    Measured: 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.

  3. Duration of Response (DOR) [Phase 2a]

    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.

    Measured: 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.

  4. Median Progression Free Survival (PFS) [Phase 2a]

    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.

    Measured: Disease is evaluated and followed-up every 8 weeks, with median of 20.04 months and maximum of 35.64 months.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Aug 2016 (estimated)
  2. Study start24 Aug 2016
  3. Primary completion3 Dec 2020
  4. Study completionSep 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
41 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02871791
Sponsor's protocol ID
16-177
Status last verified
Aug 2022
First submitted
29 Jun 2016
Last updated
29 Aug 2022
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • Gomez Tejeda Zanudo J, Barroso-Sousa R, Jain E, Jin Q, Li T, Buendia-Buendia JE, Pereslete A, Abravanel DL, Ferreira AR, Wrabel E, Helvie K, Hughes ME, Partridge AH, Overmoyer B, Lin NU, Tayob N, Tolaney SM, Wagle N. Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial. Nat Commun. 2024 Mar 19;15(1):2446. doi: 10.1038/s41467-024-45835-6.

    PubMed 38503755

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Palbociclib, Everolimus and Exemestane in people with Human Epidermal Growth Factor 2 Negative Carcinoma of Breast and Hormone Receptor (HR)-Positive Breast Cancer, run by Dana-Farber Cancer Institute at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 33 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Aug 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02871791, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Aug 2022.

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