Avelumab or Hydroxychloroquine With or Without Palbociclib to Eliminate Dormant Breast Cancer

NCT04841148

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Breast Cancer
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- Bone marrow aspirate after completion of all definitive therapy demonstrates detectable DTCs (via IHC) as performed by central laboratory assessment at University of Pennsylvania.

- History of stage II-III histologically-confirmed ER+/Her2 neg invasive breast cancer with no evidence of recurrent local or distant disease (by American Joint Committee on Cancer 7th edition). Patients with bilateral breast cancer are eligible, so long as both cancers are ER+/Her2 neg, at least one meets other eligibility criteria and patient is treated with curative intent. For patients who undergo neoadjuvant therapy, eligibility is based upon pathologic stage of residual disease at surgery.

- ER+/Her2 neg receptor status on breast primary tumor (by American Society of Clinical Oncology/College of American Pathologists guidelines). Any partial response (PR) status is allowed. Tumors that are ER negative and PR positive are not eligible. Patients who undergo neoadjuvant therapy are eligible if either the pre-treatment biopsy or residual disease at surgery is ER+/Her2 neg.

- Patients must have completed all primary and adjuvant therapy (including surgery, chemotherapy, and radiation) with the exception of adjuvant endocrine therapy. Prior treatment-related toxicity must be resolved to ≤ Grade 1 with the exception of alopecia and peripheral neuropathy, prior to study enrollment.

- Patients may have received prior CDK4/6 inhibitor therapy with an agent other than Palbociclib. Patients must have discontinued CDK4/6 inhibitor at least 6 months prior to screening.

- Patients must be receiving adjuvant endocrine therapy at the time of enrollment. Patients are eligible to enroll within 2-7 years after initiation of adjuvant endocrine therapy. Use of tamoxifen as adjuvant endocrine therapy during study treatment is not allowed on hydroxychloroquine arms due to the potential drug-drug interaction with hydroxychloroquine. However, patients on tamoxifen at the time of screening may enroll on the treatment trial if switched to an aromatase inhibitor at least 21 days prior to starting study therapy in the event patient is randomized to a hydroxychloroquine containing arm. Premenopausal patients on concurrent ovarian suppression are eligible. Patients on any other adjuvant endocrine therapy, including any investigational therapy, are ineligible.

- Patients receiving bone modifying agents (bisphosphonates or rank-ligand inhibitors) at the time of screening may continue this therapy. Bone modifying agents may not be initiated while receiving study treatment.

- No concurrent enrollment on another investigational therapy clinical trial.

- Men and women, age ≥ 18 years.

- No contraindications to the study medications (refer to Section 7.2) or uncontrolled medical illness.

- Adequate bone marrow, liver, and renal function and other parameters.

- Ability to speak and understand English

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- Patients with a history of another prior invasive breast cancer are ineligible.
Patients with prior Ductal carcinoma in situ (DCIS) of the breast are eligible if this
was diagnosed > 5 years prior to enrollment. Patients with prior invasive malignancy
other than breast cancer are eligible if they have been disease-free for at least 5
years prior to enrollment.


- Patients receiving chronic, high dose systemic treatment with corticosteroids defined
as: chronic use of cortisone >50mg; hydrocortisone >40mg, prednisone >10mg,
methylprednisone >8mg or dexamethasone >1.5mg; or another immunosuppressive agent.
Topical or inhaled corticosteroids are allowed.


- EKG demonstrating QT interval corrected (QTC) > 480 ms


- Any severe and/or uncontrolled medical conditions or other conditions that could
affect subject participation in the study including:


- Chronic autoimmune disease


- History or evidence of increased cardiovascular risk including any of the
following:


- Current clinical significant uncontrolled arrhythmias. Exception: Subjects
with controlled atrial fibrillation


- History of acute coronary syndromes (including myocardial infarction and
unstable angina), coronary angioplasty, or stenting within 6 months prior to
enrollment


- Current ≥ Class II congestive heart failure as defined by New York Heart
Association


- History of pneumonitis/interstitial lung disease or severely impaired lung
function with a previously documented spirometry and Diffusing Capacity of Lung
for Carbon Monoxide (DLCO) that is 50% of the normal predicted value (these tests
not required at screening; prior results, if performed for standard of care
should be referenced) and/or O2 saturation that is 88% or less at rest on room
air


- Uncontrolled diabetes


- Active (acute or chronic) or uncontrolled severe infections


- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis


- HIV positive patient who are receiving combination anti-retroviral therapy are
ineligible because of the potential for pharmacokinetic interactions or increased
immunosuppression with Palbociclib. However, HIV per se is not a contraindication
to study participation and HIV testing is not required.


- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of hydroxychloroquine (e.g., ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small
bowel resection)


- Patients with an active, bleeding diathesis. Patients receiving therapeutic
anticoagulation are not eligible for study participation.


- History of retinopathy or retinal vein occlusion


- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods.

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Advanced Information
Descriptive Information
Brief Title  ICMJE Avelumab or Hydroxychloroquine With or Without Palbociclib to Eliminate Dormant Breast Cancer
Official Title  ICMJE A Phase II Trial of Avelumab or Hydroxychloroquine With or Without Palbociclib to Eliminate Dormant Breast Cancer (PALAVY)
Brief Summary This clinical trial will assess the safety and early efficacy of Hydroxychloroquine or Avelumab, with or without Palbociclib, in early-stage ER+ breast cancer patients who are found to harbor disseminated tumor cells (DTCs) in the bone marrow after definitive surgery and standard adjuvant therapy.
Detailed Description

The overarching goal of this clinical trial is to reduce the incidence of incurable recurrent metastatic breast cancer by targeting the precursors of these recurrences, bone marrow disseminated tumor cells (DTCs) present after definitive treatment. This trial targets unique mechanisms by which DTCs maintain a dormant phenotype (autophagy) and by which they escape dormancy (upregulation of the cyclin-dependent kinase4/6 (CDK4/6) pathway and microenvironmental factors such as immune evasion). The selection of these agents is based upon strong preclinical data demonstrating the relevance of autophagy (inhibited by HCQ), the CDK4/6 pathway (inhibited by palbociclib) and the programmed cell death-1 (PD-1)/Programmed death-ligand 1 (PD-L1) immune checkpoint pathway (blocked by avelumab) as critical mechanisms of cellular and immunological tumor dormancy.

The phase II trial is designed to provide "proof of concept" and estimates of effect of various combinations and durations of these therapies on bone marrow DTCs as a surrogate for ultimate reduction in recurrence. The correlative science aims will provide additional insight into the relationship between the primary tumor and both the biology of DTCs and host immune surveillance for target validation and development, as well as evaluate the role of additional biomarkers both in the bone marrow (with a novel flow-based assay), and in the peripheral circulation (including both circulating tumor cells and cell-free DNA), to identify patients with minimal residual disease (MRD) and targets for intervention and measurement of DTC response.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: HCQ
    600 mg tablets twice daily D1-28 of each 28-day cycle
    Other Names:
    • Hydroxychloroquine sulfate
    • Plaquenil
  • Drug: Avelumab
    10 mg/kg, IV, D1 and D15 of each 28-day cycle
    Other Names:
    • MSB0010718C
    • Bavencio
  • Drug: Palbociclib
    125 mg capsule daily, by mouth on D1-21 concurrently with Avelumab. Or 75 mg capsule daily, by mouth on D1-28 concurrently with HCQ.
    Other Name: Ibrance
Study Arms  ICMJE
  • Experimental: HCQ
    Patients will receive HCQ, 600 mg twice daily D1-28 of each 28-day cycle.
    Intervention: Drug: HCQ
  • Experimental: Avelumab
    Patients will receive Avelumab, 10 mg/kg, IV, D1 and D15 of each 28-day cycle.
    Intervention: Drug: Avelumab
  • Experimental: Palbociclib and Avelumab
    Patients will receive Palbociclib 125 mg daily, by mouth on D1-21 concurrently with Avelumab, 10 mg/kg IV on D1 and D15 of each 28-day cycle
    Interventions:
    • Drug: Avelumab
    • Drug: Palbociclib
  • Experimental: Palbociclib and HCQ
    Patients will receive Palbociclib 75 mg daily, by mouth on D1-28 concurrently with HCQ, 600 mg twice daily D1-28 of each 28-day cycle.
    Interventions:
    • Drug: HCQ
    • Drug: Palbociclib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 7, 2021)
96
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2028
Estimated Primary Completion Date November 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Bone marrow aspirate after completion of all definitive therapy demonstrates detectable DTCs (via IHC) as performed by central laboratory assessment at University of Pennsylvania.
  • History of stage II-III histologically-confirmed ER+/Her2 neg invasive breast cancer with no evidence of recurrent local or distant disease (by American Joint Committee on Cancer 7th edition). Patients with bilateral breast cancer are eligible, so long as both cancers are ER+/Her2 neg, at least one meets other eligibility criteria and patient is treated with curative intent. For patients who undergo neoadjuvant therapy, eligibility is based upon pathologic stage of residual disease at surgery.
  • ER+/Her2 neg receptor status on breast primary tumor (by American Society of Clinical Oncology/College of American Pathologists guidelines). Any partial response (PR) status is allowed. Tumors that are ER negative and PR positive are not eligible. Patients who undergo neoadjuvant therapy are eligible if either the pre-treatment biopsy or residual disease at surgery is ER+/Her2 neg.
  • Patients must have completed all primary and adjuvant therapy (including surgery, chemotherapy, and radiation) with the exception of adjuvant endocrine therapy. Prior treatment-related toxicity must be resolved to ? Grade 1 with the exception of alopecia and peripheral neuropathy, prior to study enrollment.
  • Patients may have received prior CDK4/6 inhibitor therapy with an agent other than Palbociclib. Patients must have discontinued CDK4/6 inhibitor at least 6 months prior to screening.
  • Patients must be receiving adjuvant endocrine therapy at the time of enrollment. Patients are eligible to enroll within 2-7 years after initiation of adjuvant endocrine therapy. Use of tamoxifen as adjuvant endocrine therapy during study treatment is not allowed on hydroxychloroquine arms due to the potential drug-drug interaction with hydroxychloroquine. However, patients on tamoxifen at the time of screening may enroll on the treatment trial if switched to an aromatase inhibitor at least 21 days prior to starting study therapy in the event patient is randomized to a hydroxychloroquine containing arm. Premenopausal patients on concurrent ovarian suppression are eligible. Patients on any other adjuvant endocrine therapy, including any investigational therapy, are ineligible.
  • Patients receiving bone modifying agents (bisphosphonates or rank-ligand inhibitors) at the time of screening may continue this therapy. Bone modifying agents may not be initiated while receiving study treatment.
  • No concurrent enrollment on another investigational therapy clinical trial.
  • Men and women, age ? 18 years.
  • No contraindications to the study medications (refer to Section 7.2) or uncontrolled medical illness.
  • Adequate bone marrow, liver, and renal function and other parameters.
  • Ability to speak and understand English

Exclusion Criteria:

  • Patients with a history of another prior invasive breast cancer are ineligible. Patients with prior Ductal carcinoma in situ (DCIS) of the breast are eligible if this was diagnosed > 5 years prior to enrollment. Patients with prior invasive malignancy other than breast cancer are eligible if they have been disease-free for at least 5 years prior to enrollment.
  • Patients receiving chronic, high dose systemic treatment with corticosteroids defined as: chronic use of cortisone >50mg; hydrocortisone >40mg, prednisone >10mg, methylprednisone >8mg or dexamethasone >1.5mg; or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
  • EKG demonstrating QT interval corrected (QTC) > 480 ms
  • Any severe and/or uncontrolled medical conditions or other conditions that could affect subject participation in the study including:

    • Chronic autoimmune disease
    • History or evidence of increased cardiovascular risk including any of the following:

      • Current clinical significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation
      • History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrollment
      • Current ? Class II congestive heart failure as defined by New York Heart Association
    • History of pneumonitis/interstitial lung disease or severely impaired lung function with a previously documented spirometry and Diffusing Capacity of Lung for Carbon Monoxide (DLCO) that is 50% of the normal predicted value (these tests not required at screening; prior results, if performed for standard of care should be referenced) and/or O2 saturation that is 88% or less at rest on room air
    • Uncontrolled diabetes
    • Active (acute or chronic) or uncontrolled severe infections
    • Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
    • HIV positive patient who are receiving combination anti-retroviral therapy are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with Palbociclib. However, HIV per se is not a contraindication to study participation and HIV testing is not required.
    • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of hydroxychloroquine (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
    • Patients with an active, bleeding diathesis. Patients receiving therapeutic anticoagulation are not eligible for study participation.
    • History of retinopathy or retinal vein occlusion
  • Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lauren Bayne215-349-5398[email protected]
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04841148
Other Study ID Numbers  ICMJE TBCRC 046
01121 ( Other Identifier: University of Pennsylvania )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Abramson Cancer Center of the University of Pennsylvania
Study Sponsor  ICMJE Abramson Cancer Center of the University of Pennsylvania
Collaborators  ICMJE
  • Johns Hopkins University
  • Translational Breast Cancer Research Consortium
  • Pfizer
  • Breast Cancer Research Foundation
Investigators  ICMJE
Principal Investigator:Angela DeMichele, MDUniversity of Pennsylvania
PRS Account Abramson Cancer Center of the University of Pennsylvania
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP