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

NCT03591276 | Unknown Phase 1 FDA Drug

• 1 other identifier: 310-17-SZMC
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Breast Cancer

Keywords

metastatic breast cancer; immune check point inhibitors; chemotherapy; liposomal doxorubicin; pharmacokinetics; Anti-PD1 antibodies

Outcome Measures

Primary Outcomes (2)

• 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,

  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.

  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.

  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.

  During Cycle 1 (between days 1 and 22), and Cycle 3 (between days 42 and 63), each cycle is 21 days

Study Arms (1)

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.

Drug: Chemotherapy Drugs, Cancer

Interventions

Chemotherapy Drugs, Cancer DRUG

IV pembrolizumab 200 mg flat dose with IV PLD 30 mg/m2 (chemotherapy drugs) every 3 weeks in eligible breast cancer patients.

Also known as: Immunotherapy Antibodies, Cancer

Pembrolizumab and PLD

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• \. 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.
• \. Have received at least two lines of hormonal therapy, one of which had included aromatase inhibitors.
• \. May have received none or up to 2 lines of chemotherapy (excluding any chemotherapy given in adjuvant or pre-operative-neoadjuvant settings).
• \. 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.
• \. 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.
• \. Understanding of study procedures and willingness to comply throughout the entire course of the study and to provide written informed consent.

You may not qualify if:

• 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).
• 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.

Sponsors & Collaborators

• Shaare Zedek Medical Center: lead

Study Sites (1)

Shaare Zedek Medical Center

Jerusalem, 91031, Israel

RECRUITING

Related Publications (4)

• 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.

  PMID: 14998846 RESULT

• Tahover 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.

  PMID: 25415656 RESULT

• Rios-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.

  PMID: 26408258 RESULT

• Gabizon 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.

  PMID: 27912846 RESULT

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Antineoplastic Agents

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Alberto A Gabizon, MD, PhD

  Shaare Zedek MC

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alberto A. Gabizon, MD, PhD

CONTACT

972508685036; alberto.gabizon@gmail.com

Yair Plesser, MSc

CONTACT

97226555362; yairp@szmc.org.il

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 26, 2018
• First Posted: July 19, 2018
• Study Start: April 18, 2019
• Primary Completion: April 15, 2021
• Study Completion: June 15, 2021
• Last Updated: October 23, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)