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Phase 1b Study of Pegylated Liposomal Doxorubicin and Pembrolizumab in Endocrine-resistant Breast Cancer (KEYDOX)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03591276
Recruitment Status : Unknown
Verified October 2020 by Shaare Zedek Medical Center.
Recruitment status was:  Recruiting
First Posted : July 19, 2018
Last Update Posted : October 23, 2020
Information provided by (Responsible Party):
Shaare Zedek Medical Center

Brief Summary:

Very few patients with endocrine-resistant, hormone-receptor positive metastatic breast cancer respond to single agent immunotherapy. Responses to chemotherapy are usually of short duration. Combining immunotherapy with chemotherapy that has minimal immunosuppressive effect, it may be possible to achieve higher response rates while keeping the immune-associated pattern of long durations of response.

This will be a single-center phase 1b study to evaluate the tumor response and appropriate dose of a chemo-immunotherapy regime consisting of treatment with pegylated liposomal doxorubicin (PLD) and pembrolizumab-based in endocrine-resistant breast cancer (ERBC) patients.

Up to 15 female patients, ages 18 and above, with pathological diagnosis of breast cancer, estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2-) negative subtype, stage III non-operable, or stage IV disease, who have received at least two lines of hormonal therapy, one of which included aromatase inhibitors will be eligible for enrollment to this single arm study.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Drug: Chemotherapy Drugs, Cancer Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study of Combination Chemo-immunotherapy With Pegylated Liposomal Doxorubicin (Doxil/Caelyx) and Pembrolizumab (Keytruda) in Metastatic Endocrine-resistant Breast Cancer
Actual Study Start Date : April 18, 2019
Estimated Primary Completion Date : April 15, 2021
Estimated Study Completion Date : June 15, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Pembrolizumab and PLD

Cohort S1: IV pembrolizumab 200 mg flat dose with IV PLD 30 mg/m2 every 3 weeks.

Reduced Dose Cohort (R1)*: IV pembrolizumab 200 mg flat dose with IV PLD 24 mg/m2 every 3 weeks.

*Subjects will be recruited into the R1 cohort only if DLT is reported in 2 or more subjects during the first 2 cycles of treatment in the first 6 patients of the S1 cohort.

Drug: Chemotherapy Drugs, Cancer
IV pembrolizumab 200 mg flat dose with IV PLD 30 mg/m2 (chemotherapy drugs) every 3 weeks in eligible breast cancer patients.
Other Name: Immunotherapy Antibodies, Cancer

Primary Outcome Measures :
  1. To establish a safe dose of PLD when delivered in combination with pembrolizumab [ Time Frame: At the end of Cycle 2 (day 42), each cyle is 21 days ]
    A dose will be considered safe when the number of Participants With Treatment-Related Adverse Events grades 3 or 4, as assessed by CTCAE v4.0, will be less than 2 per 6-patient cohort. Our hypothesis is that treatment with pembrolizumab will be compatible with the standard recommended dose of PLD,

  2. To evaluate the Tumor Response Rate according to Response Evaluation Criteria in Solid Tumors (RECIST) after 9 weeks (3 cycles) of treatment in patients with measurable disease. [ Time Frame: At the end of Cycle 3 (day 63), each cycle is 21 days ]
    Th response rate will be evaluated after 9 weeks (3 cycles) by RECIST. Our hypothesis is that the response rate of the combination will be higher than expected from each agent alone.

Secondary Outcome Measures :
  1. To evaluate the safety and DLT of the PLD and pembrolizumab combination, as indicated by the number of study participants with treatment-related Adverse Events, and the class of Adverse Events as assessed by CTCAE v4.0. [ Time Frame: At the end of Cycle 2 (day 42), each cycle is 21 days ]
    The safety profile of PLD and pembrolizumab will be evaluated by the number of study participants with treatment-related Adverse Events, and the class of Adverse Events as assessed by CTCAE v4.0. Our hypothesis is that it will remain unchanged when given in combination, as compared to what expected for each drug alone.

  2. To characterize the PK of PLD when delivered in combination with pembrolizumab, by measuring and comparing the Area under the curve (AUC) for doxorubicin (liposomal) obtained during Cycles 1 and 3. [ Time Frame: During Cycle 1 (between days 1 and 22), and Cycle 3 (between days 42 and 63), each cycle is 21 days ]
    The PK of PLD will be evaluated by quantitation of doxorubicin (liposomal) in plasma samples and calculation of the AUC. Hypothesis: The PK profile of PLD may be modified by pembrolizumab during the course of therapy due to indirect effects on the mononuclear-phagocyte system (MPS) which plays an important role in PLD clearance. This will translate into a decrease or increase of AUC when the results of the 1st and 3rd cycles are compared.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Have pathological diagnosis of breast cancer, ER positive (%ER+ cells≥1%, Allred score ≥3), Her2 negative subtype, locally advanced (stage III non-operable), or metastatic (stage IV) disease.
  2. Have measurable disease on computed tomography (CT) or positron emission tomography-computed tomography (PET-CT) scan.

2. Be 18 years of age on day of signing informed consent. 3. Have measurable disease based on RECIST 1.1. 4. Have Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. 5. Have an estimated life expectancy of at least 3 months. 6. Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 10 days of treatment initiation.

7. Have received at least two lines of hormonal therapy, one of which had included aromatase inhibitors.

8. May have received none or up to 2 lines of chemotherapy (excluding any chemotherapy given in adjuvant or pre-operative-neoadjuvant settings).

9. Have a ≥21-day treatment-free interval from chemotherapeutic treatment. 10. Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

11. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2, for the course of the study through 120 days after the last dose of study medication.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

12. Understanding of study procedures and willingness to comply throughout the entire course of the study and to provide written informed consent.

Exclusion Criteria:

  1. Has known hypersensitivity to the study drugs or to any of their excipients.
  2. Has congestive heart failure (New York Heart Association [NYHA] Class IV) or left ventricular ejection fraction (LVEF) ≤40%.
  3. Has chronic obstructive pulmonary disease (COPD) >Stage 3 (forced expiratory volume in 1 second [FEV1] <50%, forced expiratory volume 1/forced vital capacity [FEV1/FVC] <70%).
  4. Has cirrhosis (Child-Pugh Class C score).
  5. Has serum albumin level < 2.5 g/dl.
  6. Has a known history of HIV (HIV 1/2 antibodies).
  7. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  8. Has evidence of active bleeding or bleeding diathesis.
  9. Concomitant use of any other chemotherapy (except for PLD) or hormonal therapy during the study
  10. Uncontrolled ascites (defined as 2 or more palliative taps within 30 days of screening).
  11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  12. Continuous steroid treatment for other than brain metastases requiring daily corticosteroid dose ≥ 10 mg prednisone or corticosteroid-equivalent per day.
  13. Anthracycline treatment (doxorubicin, epirubicin, mitoxantrone, PLD) in metastatic setting.
  14. Less than 6 months from last treatment with anthracyclines in adjuvant or neo-adjuvant setting.
  15. Use of any investigational drug within 28 days prior to study entry.
  16. Diagnosis of any other malignancy within 5 years prior to registration, except for adequately treated basal cell or squamous cell skin cancer, superficial melanoma, or carcinoma in situ of the breast or of the cervix.
  17. Severe gastrointestinal conditions such as clinical or radiological evidence of bowel obstruction within 4 weeks prior to study entry, or uncontrolled diarrhea in the last 4 weeks prior to enrollment.
  18. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
  19. Has a diagnosis of immunodeficiency or is receiving any immunosuppressive therapy (except for prednisone ≤10 mg/day or equivalent) within 7 days prior to the first dose of trial treatment.
  20. Has a known history of active Bacillus Tuberculosis.
  21. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier.
  22. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 3 weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously administered agent.

    Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

    Note: If the subject underwent major surgery, she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

  23. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin or melanoma that have undergone potentially curative therapy or in situ cervical or bladder cancer.
  24. Has known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases are eligible for recruitment provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and may be receiving dexamethasone at a dose ≤4 mg/day prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  25. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  26. Has a known history of, or any evidence of active, non-infectious pneumonitis.
  27. Has an active serious infection or an active infection requiring systemic therapy.
  28. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  29. Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  30. Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  31. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03591276

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Contact: Alberto A. Gabizon, MD, PhD 972508685036 alberto.gabizon@gmail.com
Contact: Yair Plesser, MSc 97226555362 yairp@szmc.org.il

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Shaare Zedek Medical Center Recruiting
Jerusalem, Israel, 91031
Contact: Alberto Gabizon, MD, PhD    0508685036    alberto.gabizon@gmail.com   
Contact: Yair Plesser    0505204342    yairp@szmc.org.il   
Sponsors and Collaborators
Shaare Zedek Medical Center
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Principal Investigator: Alberto A Gabizon, MD, PhD Shaare Zedek MC
Publications of Results:
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Responsible Party: Shaare Zedek Medical Center
ClinicalTrials.gov Identifier: NCT03591276    
Other Study ID Numbers: 310-17-SZMC
First Posted: July 19, 2018    Key Record Dates
Last Update Posted: October 23, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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.: Yes
Keywords provided by Shaare Zedek Medical Center:
metastatic breast cancer
immune check point inhibitors
liposomal doxorubicin
Anti-PD1 antibodies
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents