Metastatic Breast CancerPhase 1/2KEYDOXNCT03591276
Phase 1b Study of Pegylated Liposomal Doxorubicin and Pembrolizumab in Endocrine-resistant Breast Cancer
A Phase 1/2 study testing Chemotherapy Drugs, Cancer in people with Metastatic Breast Cancer, run by Shaare Zedek Medical Center at 1 site in Israel.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Metastatic Breast Cancer
- What is being tested?
- Chemotherapy Drugs, Cancer
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 1 siteIsrael
- Study dates
- 18 Apr 2019to 15 Jun 2021
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
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
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
- 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.
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- 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.
Who cannot join
- Has known hypersensitivity to the study drugs or to any of their excipients.
- Has congestive heart failure (New York Heart Association [NYHA] Class IV) or left ventricular ejection fraction (LVEF) ≤40%.
- 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%).
- Has cirrhosis (Child-Pugh Class C score).
- Has serum albumin level < 2.5 g/dl.
- Has a known history of HIV (HIV 1/2 antibodies).
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- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- Has evidence of active bleeding or bleeding diathesis.
- Concomitant use of any other chemotherapy (except for PLD) or hormonal therapy during the study
- Uncontrolled ascites (defined as 2 or more palliative taps within 30 days of screening).
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
- Continuous steroid treatment for other than brain metastases requiring daily corticosteroid dose ≥ 10 mg prednisone or corticosteroid-equivalent per day.
- Anthracycline treatment (doxorubicin, epirubicin, mitoxantrone, PLD) in metastatic setting.
- Less than 6 months from last treatment with anthracyclines in adjuvant or neo-adjuvant setting.
- Use of any investigational drug within 28 days prior to study entry.
- 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.
- 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.
- 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.
- 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.
- Has a known history of active Bacillus Tuberculosis.
- 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.
- 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.
- 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.
- 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.
- 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.
- Has a known history of, or any evidence of active, non-infectious pneumonitis.
- Has an active serious infection or an active infection requiring systemic therapy.
- 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.
- Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- 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.
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Israel1 site, 1 recruiting
- Recruiting
Shaare Zedek Medical Center
Jerusalem, 91031
Alberto Gabizon, MD, PhD, 0508685036, alberto.gabizon@gmail.com
Yair Plesser, 0505204342, yairp@szmc.org.il
About this study
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
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.
Read the detailed description
This will be a single-center phase 1b study to evaluate the tumor response and appropriate dose of combined treatment with pembrolizumab and pegylated liposomal doxorubicin (PLD) in endocrine-resistant breast cancer (ERBC) patients.
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 the study.
The total number of patients in the study will be 15 patients. The study diagram is shown in Figure 1. After signing the informed consent, eligible subjects will be successively assigned, in order of accrual, to a dosing cohort. Six subjects will be enrolled in the Start Cohort (Cohort S1), and receive: intravenous (IV) pembrolizumab 200 mg flat dose with IV pegylated liposomal doxorubicin (PLD) 30 mg/m2, every 3 weeks. Toxicity will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events Ver. 4.0 (NCI-CTCAE).
If during the first 2 cycles of treatment (the first 6 weeks) in the Start Cohort (Cohort S1), up to one subject out of the 6 in the cohort will develop a dose-limiting toxicity (DLT; defined as grade-4 hematological adverse events (AEs), or grade 3 non-hematological AEs [stomatitis, hand and foot syndrome] in the first 2 cycles), the drug combination's safety profile will be deemed acceptable and up to 9 more subjects will be recruited in the cohort (Expanded Start Cohort S1) and will receive the same dose to help establish the rate of Tumor Response and to confirm safety.
If during the first 2 cycles of treatment in the Start Cohort (Cohort S1) a DLT will be observed in 2 or more patients out of the initial 6 patients enrolled into this cohort, Cohort S1 will be discontinued, and a Reduced Dose Cohort (Cohort R1), will be accrued where the dose of PLD will be reduced by 20% to 24 mg/m2 (IV pembrolizumab 200 mg flat dose with IV PLD 24 mg/m2 every 3 weeks). Initially, 6 patients will be accrued to Cohort R1. If during the first 2 cycles of treatment (the first 6 weeks) in the Reduced Dose Cohort (Cohort R1), up to one subject out of the 6 in the cohort will develop a DLT, the drug combination's safety profile will be deemed acceptable and up to 7 more subjects will be recruited in the cohort (Expanded Reduced Cohort R1) to help establish the rate of Tumor Response and to confirm safety of the reduced dose.
If during the first 2 cycles of treatment in Cohort R1, a DLT would be again observed in 2 or more subjects, the study will be terminated (refer to Figure 1 for the study diagram).
Note: Only the first 2 cycles will be considered for safety clearance of any Cohort. If an additional DLT occurs in the 3rd cycle, the dose will be individually modified if the affected patient has stable disease (SD) or partial response/complete response (PR/CR), and the patient will continue to the extended phase of the study.
The 3 first cycles of treatment (first 9 weeks) constitute the main phase of the study during which most of the study objectives will be reached (safe dose clearance, tumor response rate characterization of DLT's, pharmacokinetic [PK] analysis of PLD). Patients will return to the study center on days 7 and 14 of cycles 1, 2 and 3, for monitoring assessments and for clinical laboratory evaluations. Blood samples will be collected on study visits for measurement of PLD concentrations at various time points during cycle 1. For each subject, subsequent dosing will take place 21 days after the previous treatment, provided patients are deemed fit to be dosed again.
For responding or stable patients, the extended phase of the study consists of 9 additional cycles (27 more weeks) during which further safety information, duration of response, progression-free survival (PFS) time, and other pertinent data will be collected. During both phases of the study and beyond, information on survival and post-study treatments will be collected until death. Information on potentially predictive biomarkers of treatment response (and duration of response) will be gathered all along the study.
All patients receiving two or more cycles will be followed-up for survival until death. Study treatment may continue until disease progression, unacceptable toxicity, patient refusal, patient loss to follow up, or termination of the study by the Sponsor or Investigator, whichever comes first. Pembrolizumab may be continued beyond disease progression. PLD will not be continued beyond disease progression.
- Conditions
- Metastatic Breast Cancer
- Being tested
- Chemotherapy Drugs, Cancer
- Keywords
- metastatic breast cancer, immune check point inhibitors, chemotherapy, liposomal doxorubicin, pharmacokinetics, Anti-PD1 antibodies
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Chemotherapy Drugs, CancerDrug
Also called Immunotherapy Antibodies, Cancer
IV pembrolizumab 200 mg flat dose with IV PLD 30 mg/m2 (chemotherapy drugs) every 3 weeks in eligible breast cancer patients.
| Study group | Role | What they receive |
|---|---|---|
| Pembrolizumab and PLD | Experimental | 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. Receives: Drug: Chemotherapy Drugs, Cancer |
What is being measured
The primary outcome is the main question the study is designed to answer.
To establish a safe dose of PLD when delivered in combination with pembrolizumab
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,
Measured: At the end of Cycle 2 (day 42), each cyle is 21 days
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.
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.
Measured: At the end of Cycle 3 (day 63), each cycle is 21 days
Secondary outcomes (2)
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.
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.
Measured: At the end of Cycle 2 (day 42), each cycle is 21 days
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.
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.
Measured: During Cycle 1 (between days 1 and 22), and Cycle 3 (between days 42 and 63), each cycle is 21 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jul 2018
- Study start18 Apr 2019
- Primary completion15 Apr 2021 (estimated)
- Study completion15 Jun 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Metastatic Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- 15 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Shaare Zedek Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Alberto A Gabizon, MD, PhD, Principal investigator, Shaare Zedek MC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03591276
- Sponsor's protocol ID
- 310-17-SZMC
- Acronym
- KEYDOX
- Status last verified
- Oct 2020
- First submitted
- 26 Jun 2018
- Last updated
- 23 Oct 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. doi: 10.1093/annonc/mdh097.
PubMed 14998846Tahover E, Patil YP, Gabizon AA. Emerging delivery systems to reduce doxorubicin cardiotoxicity and improve therapeutic index: focus on liposomes. Anticancer Drugs. 2015 Mar;26(3):241-58. doi: 10.1097/CAD.0000000000000182.
PubMed 25415656Rios-Doria J, Durham N, Wetzel L, Rothstein R, Chesebrough J, Holoweckyj N, Zhao W, Leow CC, Hollingsworth R. Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. Neoplasia. 2015 Aug;17(8):661-70. doi: 10.1016/j.neo.2015.08.004.
PubMed 26408258Gabizon AA, Patil Y, La-Beck NM. New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updat. 2016 Nov;29:90-106. doi: 10.1016/j.drup.2016.10.003. Epub 2016 Oct 29.
PubMed 27912846Gabizon AA, Goldvaser H, Yaacov A, Rosengarten OS, Cherny N, Isacson R, Breuer S, Abu-Remilah A, Shmeeda H, Golomb E, Turner YN, Grinshpun A. A Phase Ib Study of Chemoimmunotherapy with Pegylated Liposomal Doxorubicin and Pembrolizumab in Estrogen Receptor-Positive Metastatic Breast Cancer. Cancer Res Commun. 2026 Jul 1;6(7):1738-1749. doi: 10.1158/2767-9764.CRC-25-0539.
PubMed 42361329
Study at a glance
From the registry record, last updated by the sponsor on 23 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03591276
- Acronym / sponsor ID
- KEYDOX / 310-17-SZMC
- Conditions
- Metastatic Breast Cancer
- Keywords
- metastatic breast cancer, immune check point inhibitors, chemotherapy, liposomal doxorubicin, pharmacokinetics, Anti-PD1 antibodies
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 15 participants (estimated)
- Lead sponsor
- Shaare Zedek Medical CenterUniversity, hospital or other
- Study start
- 18 Apr 2019 (actual)
- Primary completion
- 15 Apr 2021 (estimated)
- Study completion
- 15 Jun 2021 (estimated)
- First posted
- 19 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
This will be a single-center phase 1b study to evaluate the tumor response and appropriate dose of combined treatment with pembrolizumab and pegylated liposomal doxorubicin (PLD) in endocrine-resistant breast cancer (ERBC) patients.
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 the study.
The total number of patients in the study will be 15 patients. The study diagram is shown in Figure 1. After signing the informed consent, eligible subjects will be successively assigned, in order of accrual, to a dosing cohort. Six subjects will be enrolled in the Start Cohort (Cohort S1), and receive: intravenous (IV) pembrolizumab 200 mg flat dose with IV pegylated liposomal doxorubicin (PLD) 30 mg/m2, every 3 weeks. Toxicity will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events Ver. 4.0 (NCI-CTCAE).
If during the first 2 cycles of treatment (the first 6 weeks) in the Start Cohort (Cohort S1), up to one subject out of the 6 in the cohort will develop a dose-limiting toxicity (DLT; defined as grade-4 hematological adverse events (AEs), or grade 3 non-hematological AEs [stomatitis, hand and foot syndrome] in the first 2 cycles), the drug combination's safety profile will be deemed acceptable and up to 9 more subjects will be recruited in the cohort (Expanded Start Cohort S1) and will receive the same dose to help establish the rate of Tumor Response and to confirm safety.
If during the first 2 cycles of treatment in the Start Cohort (Cohort S1) a DLT will be observed in 2 or more patients out of the initial 6 patients enrolled into this cohort, Cohort S1 will be discontinued, and a Reduced Dose Cohort (Cohort R1), will be accrued where the dose of PLD will be reduced by 20% to 24 mg/m2 (IV pembrolizumab 200 mg flat dose with IV PLD 24 mg/m2 every 3 weeks). Initially, 6 patients will be accrued to Cohort R1. If during the first 2 cycles of treatment (the first 6 weeks) in the Reduced Dose Cohort (Cohort R1), up to one subject out of the 6 in the cohort will develop a DLT, the drug combination's safety profile will be deemed acceptable and up to 7 more subjects will be recruited in the cohort (Expanded Reduced Cohort R1) to help establish the rate of Tumor Response and to confirm safety of the reduced dose.
If during the first 2 cycles of treatment in Cohort R1, a DLT would be again observed in 2 or more subjects, the study will be terminated (refer to Figure 1 for the study diagram).
Note: Only the first 2 cycles will be considered for safety clearance of any Cohort. If an additional DLT occurs in the 3rd cycle, the dose will be individually modified if the affected patient has stable disease (SD) or partial response/complete response (PR/CR), and the patient will continue to the extended phase of the study.
The 3 first cycles of treatment (first 9 weeks) constitute the main phase of the study during which most of the study objectives will be reached (safe dose clearance, tumor response rate characterization of DLT's, pharmacokinetic [PK] analysis of PLD). Patients will return to the study center on days 7 and 14 of cycles 1, 2 and 3, for monitoring assessments and for clinical laboratory evaluations. Blood samples will be collected on study visits for measurement of PLD concentrations at various time points during cycle 1. For each subject, subsequent dosing will take place 21 days after the previous treatment, provided patients are deemed fit to be dosed again.
For responding or stable patients, the extended phase of the study consists of 9 additional cycles (27 more weeks) during which further safety information, duration of response, progression-free survival (PFS) time, and other pertinent data will be collected. During both phases of the study and beyond, information on survival and post-study treatments will be collected until death. Information on potentially predictive biomarkers of treatment response (and duration of response) will be gathered all along the study.
All patients receiving two or more cycles will be followed-up for survival until death. Study treatment may continue until disease progression, unacceptable toxicity, patient refusal, patient loss to follow up, or termination of the study by the Sponsor or Investigator, whichever comes first. Pembrolizumab may be continued beyond disease progression. PLD will not be continued beyond disease progression.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pembrolizumab and PLD | Experimental | Drug: Chemotherapy Drugs, CancerCohort 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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.
- 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).
Key exclusion criteria (33 listed)
- Has known hypersensitivity to the study drugs or to any of their excipients.
- Has congestive heart failure (New York Heart Association [NYHA] Class IV) or left ventricular ejection fraction (LVEF) ≤40%.
- 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%).
- Has cirrhosis (Child-Pugh Class C score).
- Has serum albumin level < 2.5 g/dl.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Chemotherapy Drugs, CancerAlso: Immunotherapy Antibodies, CancerIV pembrolizumab 200 mg flat dose with IV PLD 30 mg/m2 (chemotherapy drugs) every 3 weeks in eligible breast cancer patients. | Drug | Pembrolizumab and PLD |
Primary outcome
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,
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.
2 secondary outcomes
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
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
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Oct 2020.
- Results publication: PubMed 14998846O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. doi: 10.1093/annonc/mdh097.
- Results publication: PubMed 25415656Tahover E, Patil YP, Gabizon AA. Emerging delivery systems to reduce doxorubicin cardiotoxicity and improve therapeutic index: focus on liposomes. Anticancer Drugs. 2015 Mar;26(3):241-58. doi: 10.1097/CAD.0000000000000182.
- Results publication: PubMed 26408258Rios-Doria J, Durham N, Wetzel L, Rothstein R, Chesebrough J, Holoweckyj N, Zhao W, Leow CC, Hollingsworth R. Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. Neoplasia. 2015 Aug;17(8):661-70. doi: 10.1016/j.neo.2015.08.004.
- Results publication: PubMed 27912846Gabizon AA, Patil Y, La-Beck NM. New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updat. 2016 Nov;29:90-106. doi: 10.1016/j.drup.2016.10.003. Epub 2016 Oct 29.
- Derived from this study: PubMed 42361329Gabizon AA, Goldvaser H, Yaacov A, Rosengarten OS, Cherny N, Isacson R, Breuer S, Abu-Remilah A, Shmeeda H, Golomb E, Turner YN, Grinshpun A. A Phase Ib Study of Chemoimmunotherapy with Pegylated Liposomal Doxorubicin and Pembrolizumab in Estrogen Receptor-Positive Metastatic Breast Cancer. Cancer Res Commun. 2026 Jul 1;6(7):1738-1749. doi: 10.1158/2767-9764.CRC-25-0539.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Alberto A Gabizon, MD, PhD principal investigator
Shaare Zedek MC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Chemotherapy Drugs, Cancer in people with Metastatic Breast Cancer, run by Shaare Zedek Medical Center at 1 site in Israel.
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 9 inclusion and 33 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: looking for participants now, as of the sponsor's last update on 23 Oct 2020. 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 Israel. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Alberto A. Gabizon, MD, PhD (972508685036, alberto.gabizon@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. 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 NCT03591276, which also lists 5 linked publications.
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 23 Oct 2020.