Clinical Trials /

Durvalumab (MEDI4736) and Tremelimumab in Hormone Receptor-positive, Hypermutated Metastatic Breast Cancer Identified by Whole Exome Sequencing

NCT03608865

Description:

Abbreviated Title : Durvalumab + tremelimumab in hypermutated breast cancer Trial Phase : II Clinical Indication : Hormone receptor-positive metastatic breast cancer Trial Type : Interventional Type of control : None Route of administration : Intravenous Trial Blinding : None Treatment Groups : Durvalumab + tremelimumab Number of trial subjects : Approximately 150 patients will be prescreened with whole exome sequencing. Then 30 patients will be enrolled in the treatment phase. Estimated enrollment period : 24 months Estimated duration of trial : The sponsor estimates that the trial will require approximately 48 months from the time the first subject signs the informed consent until the last subject's last visit. Duration of Participation : 24 months Estimated average length of treatment per patient : 8 months

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab (MEDI4736) and Tremelimumab in Hormone Receptor-positive, Hypermutated Metastatic Breast Cancer Identified by Whole Exome Sequencing
  • Official Title: Phase II Trial of Durvalumab (MEDI4736) and Tremelimumab in Hormone Receptor-positive, Hypermutated Metastatic Breast Cancer Identified by Whole Exome Sequencing

Clinical Trial IDs

  • ORG STUDY ID: 4-2016-0912
  • NCT ID: NCT03608865

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
Durvalumab with Tremelimumabexperimental group

Purpose

Abbreviated Title : Durvalumab + tremelimumab in hypermutated breast cancer Trial Phase : II Clinical Indication : Hormone receptor-positive metastatic breast cancer Trial Type : Interventional Type of control : None Route of administration : Intravenous Trial Blinding : None Treatment Groups : Durvalumab + tremelimumab Number of trial subjects : Approximately 150 patients will be prescreened with whole exome sequencing. Then 30 patients will be enrolled in the treatment phase. Estimated enrollment period : 24 months Estimated duration of trial : The sponsor estimates that the trial will require approximately 48 months from the time the first subject signs the informed consent until the last subject's last visit. Duration of Participation : 24 months Estimated average length of treatment per patient : 8 months

Trial Arms

NameTypeDescriptionInterventions
experimental groupExperimentalDrug:Durvalumab + tremelimumab Dose/Potency:Durvalumab 1500mg(up to 4cycle) / tremelimumab 75mg(up to 13 cycle) Dose Frequency:Q4W Route of Administration:IV infusion Regimen/Treatment Period:Day 1 of each 4 week cycle Use:Experimental
  • Durvalumab with Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent obtained from the subject prior to performing any
             protocol-related procedures, including screening evaluations

          -  Pre or postmenopausal women with stage IV hormone receptor-positive breast cancer by
             histological or cytological confirmation

          -  Age > 19 years at time of study entry

          -  Progression after one line of any systemic therapy (endocrine, targeted or
             chemotherapy) in the metastatic setting

          -  2.1 or more nonsynonymous mutations per megabase (Mb) by WES

          -  Subject who has biopsy-accessible tumor

          -  At least one measurable lesion by RECIST 1.1. Biopsied tumor may be counted a
             measurable lesion if it is not excised

          -  Documented disease progression on the most recent therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 ~ 1

          -  Life expectancy of > 12 weeks

          -  Adequate normal organ and marrow function as defined below:

               1. Haemoglobin ≥ 9.0 g/dL

               2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)

               3. Platelet count ≥ 100 x 109/L (>100,000 per mm3)

               4. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not
                  apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent
                  hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
                  or hepatic pathology), who will be allowed only in consultation with their
                  physician.

               5. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver
                  metastases are present, in which case it must be ≤ 5x ULN

               6. Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault
                  1976) or by 24-hour urine collection for determination of creatinine clearance: ①
                  Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine
                  (mg/dL), ② Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72
                  x serum creatinine (mg/dL)

          -  Female subjects must either be of non-reproductive potential (ie, post-menopausal by
             history: ≥ 60 years old and no menses for 1 year without an alternative medical cause;
             OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of
             bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
             Otherwise, subjects must adhere to acceptable forms of birth control (a
             physician-approved contraceptive method: oral, injectable, or implantable hormonal
             contraceptive; intra-uterine device; barrier contraceptive with spermicide; or
             vasectomized partner).

          -  Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

        Exclusion Criteria:

          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site). Previous enrollment in the present study

          -  Participation in another clinical study with an investigational product during the
             last 4 weeks

          -  Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab or an
             anti-CTLA-4, including tremelimumab

          -  Previous or coexisting malignancies. However, malignancies that have been curatively
             treated >5 years prior to study entry can be included. Exceptionally, cervical cancer
             in-situ, basal cell carcinoma, papillary thyroid carcinoma and superficial bladder
             tumors (T1a and Tis) can be included anytime after curative treatment

          -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies, other investigational agent) ≤ 21 days prior to the first dose of study
             drug and within 6 weeks for nitrosourea or mitomycin C) for sufficient wash-out time

          -  Palliative radiation, whole brain radiotherapy (WBRT), or gamma knife surgery (GKS)
             for brain metastases ≤ 2 weeks prior to initiation of study medication. Major surgery
             ≤ 4 weeks or minor surgery ≤ 2 weeks prior to initiation of study medication. Majority
             or minority of surgery can be decided at the investigator's discretion. Subjects who
             received these local therapy may be enrolled after predetermined time period

          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
             electrocardiograms (ECGs) using Fredericia's Correction

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled
             corticosteroids or systemic corticosteroids at physiological doses, which are not to
             exceed 10 mg/day of prednisone, or an equivalent corticosteroid

          -  Any unresolved toxicity (≥CTCAE grade 2) from previous anti-cancer therapy. Subjects
             with irreversible toxicity that is not reasonably expected to be exacerbated by the
             investigational product may be included (e.g., hearing loss, peripherally neuropathy)

          -  Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE >Grade 1

          -  Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects
             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
             the past 2 years) are not excluded.

          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis)

          -  History of primary immunodeficiency

          -  History of allogeneic organ transplant

          -  History of hypersensitivity to durvalumab or tremelimumab

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
             bleeding diatheses including any subject known to have evidence of acute or chronic
             hepatitis A (anti-HAV antibody+), hepatitis B (HBs antigen+), hepatitis C (anti-HCV
             antibody+) or human immunodeficiency virus (HIV-1 or HIV-2 antibody+ or HTLV-1
             antibody+), or psychiatric illness/social situations that would limit compliance with
             study requirements or compromise the ability of the subject to give written informed
             consent

          -  Known history of previous clinical diagnosis of tuberculosis

          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving durvalumab or tremelimumab

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

          -  Symptomatic brain metastasis or leptomeningeal seeding. However, after WBRT or GKS for
             symptomatic brain or leptomeningeal metastases, if subjects are stable for 4 weeks
             without steroid and the dosage of anti-convulsant is stable for 4 weeks, they are
             eligible. Asymptomatic central nervous system metastases are eligible if the subject
             has no abnormal findings on neurologic examination and is not receiving corticosteroid
             therapy to control symptoms

          -  Subjects with uncontrolled seizures

          -  Female patients who are pregnant or breastfeeding or female subjects of reproductive
             potential who are not willing to employ effective birth control from screening to 180
             days after the last dose of durvalumab + tremelimumab combination therapy or 90 days
             after the last dose of durvalumab monotherapy, whichever is the longer time period
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) by RECIST 1.1
Time Frame:up to 4 years (the end of study)
Safety Issue:
Description:To evaluate objective response rate (ORR) based on RECIST 1.1 in hormone receptor-positive, hypermutated metastatic breast cancer identified by whole exome sequencing (WES) Hypothesis: Durvalumab + tremelimumab in patients with hormone receptor-positive, hypermutated metastatic breast cancer identified by WES will result in clinically meaningful ORR based on RECIST 1.1

Secondary Outcome Measures

Measure:Clinical benefit rate (CBR) by RECIST 1.1 defined by complete or partial response or stable disease for at least 24 weeks
Time Frame:every 1 year up to 4 years (the end of study)
Safety Issue:
Description:To evaluate clinical benefit rate (CBR) by RECIST 1.1 defined by complete or partial response or stable disease for at least 24 weeks
Measure:Duration of response (DoR)
Time Frame:every 1 year up to 4 years (the end of study)
Safety Issue:
Description:To evaluate duration of response (DoR)
Measure:Disease control rate (DCR) by RECIST 1.1
Time Frame:every 1 year up to 4 years (the end of study)
Safety Issue:
Description:To evaluate disease control rate (DCR) by RECIST 1.1
Measure:Progression-free survival (PFS) by RECIST 1.1
Time Frame:every 1 year up to 4 years (the end of study)
Safety Issue:
Description:To evaluate progression-free survival (PFS) by RECIST 1.1

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Yonsei University

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