Atezolizumab and Cobimetinib or Idasanutlin in Participants With Stage IV or Unresectable Recurrent Estrogen Receptor Positive Breast Cancer

Sponsor
Vanderbilt-Ingram Cancer Center (Other)
Overall Status
Terminated
CT.gov ID
NCT03566485
Collaborator
Genentech, Inc. (Industry), Stand Up To Cancer (Other)
12
1
2
29
0.4

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and best dose of idasanutlin when given together with atezolizumab, and to see how well atezolizumab and cobimetinib or idasanutlin work in treating participants with stage IV estrogen-receptor positive (ER+) breast cancer, or ER+ breast cancer that has come back (recurrent) and cannot be removed by surgery (unresectable). Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib and idasanutlin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cobimetinib or atezolizumab with idasanutlin may work better in treating participants with estrogen-receptor positive breast cancer.

Detailed Description

PRIMARY OBJECTIVES:
  1. To determine the safety and tolerability of atezolizumab and idasanutlin in patients with estrogen receptor positive (ER+) metastatic breast cancer (mBC) (Phase I).

  2. To determine the anti-tumor effect of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II).

SECONDARY OBJECTIVES:
  1. To determine the anti-tumor duration of effect of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II).

  2. To determine the safety and tolerability of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II).

EXPLORATORY OBJECTIVES:
  1. To evaluate if CD8+ T cells are enhanced in the tumor with either MEK or MDM2 inhibition (Phase II).

  2. To evaluate if MHC-I/II and/or PD-L1 expression is enhanced with MEK inhibition (Phase II).

  3. To evaluate if T cell chemotractants (CCL5, CXCL9,10,11,13) are upregulated upon MDM2 antagonism (Phase II).

  4. To determine if baseline or changes in PDL1 expression, MHC expression, presence of tumor infiltrating lymphocytes, neoantigen expression/ mutation burden (using ribonucleic acid [RNA]-and whole exome sequencing), CCL5, CXCL9, CXCL10, CXCL11, and CXCL13 correlate with clinical outcome (Phase II).

  5. To determine if immunological activity of MEK inhibition can be tracked noninvasively using Zr^89-atezolizumab (Phase II).

OUTLINE: This is a phase 1, dose-escalation study of idasanutlin followed by a phase II study. Participants are assigned to 1 of 2 arms.

ARM I: Participants with TP53 gene mutation receive atezolizumab intravenously (IV) over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Participants without TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and idasanutlin PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed for 28 days.

Study Design

Study Type:
Interventional
Actual Enrollment :
12 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
BRE 17107: A Phase Ib/II Trial of Atezolizumab (an Anti-PD-L1 Monoclonal Antibody) With Cobimetinib (a MEK1/2 Inhibitor) or Idasanutlin (an MDM2 Antagonist) in Metastatic ER+ Breast Cancer
Actual Study Start Date :
Jul 10, 2018
Actual Primary Completion Date :
Dec 10, 2020
Actual Study Completion Date :
Dec 10, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase 2 (atezolizumab, cobimetinib)

Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Atezolizumab
Given by IV

Drug: Cobimetinib
Given by mouth

Experimental: Phase 1b - Atezolizumab 840mg IV + Idasanutlin 100mg PO

Drug: Atezolizumab
Given by IV

Drug: Idasanutlin
Given by mouth

Outcome Measures

Primary Outcome Measures

  1. Number of Participants With a Dose Limiting Toxicity (DLT) (Phase I) [At 28 days]

    Assessment of DLT for the patients in the atezolizumab and idasanutiln arm of the study

  2. Maximum Tolerated Dose (Phase I) [At 28 days]

    Assessment of MTD for the atezolizumab and idasanutiln combination arm of the study

  3. Recommended Phase II Dose (Phase I) [At 28 days]

    Assessment of recommended phase II dose for the atezolizumab and idasanutiln combination arm of the study

  4. Overall Response Rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST]1.1) (Phase II) [Up to 28 days after completion of study treatment, for a total of 2 years]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measure the rate (%) of complete and partial responses seen in patients with measurable disease. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

  1. Clinical Benefit Rate (CBR) (Phase II) [At 6 months]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measure the rate (%) of complete and partial responses + stability of disease at 6 months seen in patients with measurable disease. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

  2. Immune Related Response Criteria (irRC) (Phase II) [Up to 28 days after completion of study treatment, for a total of 2 years]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measure the rate (%) of immune-related complete and partial responses seen in patients with measurable disease

  3. Progression-free Survival (PFS) (Phase II) in Days [At 12 months]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measuring the interval (in months) between treatment initiation and disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1).

  4. Overall Survival (OS) (Phase II) in Days [At 12 months]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measuring the interval (in months) between treatment initiation and death from any cause

  5. Number of Adverse Events (Phase II) [Up to 28 days after completion of study treatment, for a total of 2 years]

    Assessment of adverse events throughout the phase II study

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
  • Signed and dated written informed consent.

  • Subjects ≥ 18 years of age.

  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

  • Clinical stage IV invasive mammary carcinoma or unresectable locoregional recurrence of invasive mammary carcinoma that is:

  • ER/PR-positive (> 1% cells) by IHC and HER2 negative per ASCO guidelines (by IHC or FISH)

  • Previously exposed to an aromatase inhibitor (AI) or a selective estrogen-receptor modulator/ downregulator (SERM; SERD) + a CDK4/6 inhibitor

  • Appropriate candidates for chemotherapy

  • Amenable to biopsy at the time of study entry

  • Adequate organ function including:

  • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L

  • Platelets ≥ 100 × 109/L

  • Hemoglobin ≥ 9/g/dL (may have been transfused)

  • Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN)

  • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases are present)

  • Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50 mL/min as calculated using the Cockcroft-Gault (CG) equation

  • Thyroid Stimulating Hormone (TSH) ≤ 1 x ULN

  • Amylase ≤ 1 x ULN

  • Lipase ≤ 1 x ULN

  • CPK ≤ 1.5 x ULN

  • LVEF (echo) ≥ LLN (Cobi arm only)

  • Female patients of childbearing potential must agree to use at least two methods of acceptable contraception with a failure rate of < 1% per year from 15 days prior to first trial treatment administration until at least 5 months after study participant's final dose of study drugs. See appendix C for details.

Note: Females of childbearing potential are defined as those who are not surgically sterile or post-menopausal (i.e. patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months without an alternative medical cause). Post-menopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women.

  • Patients unable to read/write in English are eligible to participate in the overall study but will not participate in the Patient-Reported Outcome questionnaires throughout the trial

  • Re-enrollment of a subject that has discontinued the study as a pre-treatment screen failure (i.e. a consented patient who did not receive study drugs) is permitted. If re-enrolled, the subject must be re-consented. Only the screening procedures performed outside of protocol-specified timing must be repeated.

Exclusion Criteria:
  • Prior therapy with anti-PD-L1 and anti-PD1 antibodies, MEK inhibitors or MDM2 antagonists.

  • No more than 3 lines of chemotherapy in the metastatic setting

  • No concurrent anticancer therapy. Required washout from prior therapy:

  • Endocrine therapy: no required wash-out

  • Chemotherapy: 14 days

  • Major surgery: 14 days (provided wound healing is adequate)

  • Radiation: 7 days

  • Investigational/Biologic Therapy (half -life ≤ 40 hours): 14 days

  • Investigational/Biologic Therapy (half -life > 40 hours): 28 days

  • Use of corticosteroids or immunosuppressive medication is exclusionary, except the following in the absence of active autoimmune disease:

  • Subjects are permitted the use of corticosteroids with minimal systemic absorption (e.g. topical, ocular, intra-articular, intranasal, and inhaled);

  • Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent are permitted;

  • Adrenal replacement steroid doses including doses > 10 mg daily prednisone are permitted;

  • A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT scan premedication against contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.

  • Previous malignant disease other than breast cancer within the last 5 years, with the exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or low-risk cancers considered curatively treated (i.e. complete remission achieved at least 2 years prior to first dose of study drugs AND additional therapy not required while receiving study treatment).

  • All subjects with brain metastases, except those meeting the following criteria:

  • Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment

  • No history of intracranial or spinal cord hemorrhage

  • No evidence of interim CNS disease progression

  • Metastasis to the midbrain, pons, and medulla

  • No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable.

  • Subjects must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent)

  • Receipt of any organ transplantation including allogeneic stem-cell transplantation.

  • Significant acute or chronic infections including, among others:

  • Known history of testing positive for human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS).

  • Active tuberculosis

  • Positive test for hepatitis B virus (HBV) surface antigen (and/or core antibody) and/or confirmatory hepatitis C virus (HCV) RNA (if anti-HCV antibody tested positive).

  • Active autoimmune disease with reasonable possibility of clinically significant deterioration when receiving an immunostimulatory agent:

  • Subjects with Type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.

  • Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day.

  • Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.

  • Interstitial lung disease that is symptomatic or which may interfere with the detection or management of suspected drug-related pulmonary toxicity.

  • Uncontrolled asthma [defined as having 3 or more of the following features of partially controlled asthma within 28 days prior to starting study treatment: Daytime symptoms more than twice per week, any limitation of activities, any nocturnal symptoms/awaking, need for reliever/rescue inhaler more than twice per week, or known lung function (PEF or FEV1) without administration of a bronchodilator that is < 80% predicted or personal best (if known)].

  • Current symptomatic congestive heart failure (New York Heart Association > class II), unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100mmHg). Or any of the following occurring within 6 months (180 days) prior to first dose of study drugs: Myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack. (Use of antihypertensive medication to control blood pressure is allowed.)

  • Concurrent treatment with a non-permitted drug (refer to prohibited medication list) as well as foods or supplements that are strong or moderate CYP3A4 enzyme inducers or inhibitors. Any of the above has to be discontinued at least 7 days prior to Cycle 1/ Day 1 of study treatment.

  • Requirement of anticoagulant therapy with oral vitamin K antagonists such as Coumadin (warfarin). Low-dose anticoagulants for the maintenance of patency in a central venous access device or the prevention of deep vein thrombosis or pulmonary embolism is allowed. Therapeutic use of low molecular weight heparin is allowed provided patients are safely able to interrupt it prior to biopsy procedures.

  • Persisting toxicity related to prior therapy that has not reduced to Grade 1 [National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0]; however, alopecia and sensory neuropathy Grade ≤ 2 are acceptable and Grade ≤ 2 non-hematological toxicities well controlled with medical management are allowed (for example: hypomagnesemia well controlled on magnesium replacement).

  • Known severe (Grade ≥ 3 NCI-CTCAE) hypersensitivity reactions to monoclonal antibodies, or history of anaphylaxis.

  • Vaccination within 28 days of the first dose of study drugs and while on trial is prohibited, except for administration of inactivated vaccines (for example, inactivated influenza vaccine).

  • Pregnant or breastfeeding females.

  • Known current alcohol or drug abuse

  • Prisoners or subjects who are involuntarily incarcerated.

  • Known psychiatric condition, social circumstance, or other medical condition reasonably judged by the patient's study physician to unacceptably increase the risk of study participation; or to prohibit the understanding or rendering of informed consent or anticipated compliance with scheduled visits, treatment schedule, laboratory tests and other study requirements.

  • Known risk factors for ocular toxicity, consisting of any of the following (Cobi arm only):

  • presence of serous retinopathy within 6 months of protocol enrollment

  • presence of retinal vein occlusion (RVO) within 6 months of protocol enrollment

Contacts and Locations

Locations

Site City State Country Postal Code
1 Vanderbilt-Ingram Cancer Center Nashville Tennessee United States 3720932

Sponsors and Collaborators

  • Vanderbilt-Ingram Cancer Center
  • Genentech, Inc.
  • Stand Up To Cancer

Investigators

  • Principal Investigator: Ingrid Mayer, MD, Vanderbilt-Ingram Cancer Center

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Ingrid Mayer, MD, Principal Investigator, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier:
NCT03566485
Other Study ID Numbers:
  • VICC BRE 17107
  • NCI-2018-01159
First Posted:
Jun 25, 2018
Last Update Posted:
Aug 11, 2021
Last Verified:
Aug 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details Participants were recruited to this study from July 2018 to November 2019 at Vanderbilt-Ingram Cancer Center in Nashville, TN. This study stopped early due to low accrual.
Pre-assignment Detail Twelve participants were enrolled onto this study.
Arm/Group Title Phase 2 (Atezolizumab, Cobimetinib) Phase 1b - (Atezolizumab, Idasanutlin)
Arm/Group Description Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by IV Cobimetinib: Given by mouth Atezolizumab: Given by IV Idasanutlin: Given by mouth
Period Title: Overall Study
STARTED 5 7
COMPLETED 0 0
NOT COMPLETED 5 7

Baseline Characteristics

Arm/Group Title Phase 2 (Atezolizumab, Cobimetinib) Phase 1b - (Atezolizumab, Idasanutlin) Total
Arm/Group Description Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by IV Cobimetinib: Given by mouth Atezolizumab: Given by IV Idasanutlin: Given by mouth Total of all reporting groups
Overall Participants 5 7 12
Age (Count of Participants)
<=18 years
0
0%
0
0%
0
0%
Between 18 and 65 years
4
80%
5
71.4%
9
75%
>=65 years
1
20%
2
28.6%
3
25%
Sex: Female, Male (Count of Participants)
Female
5
100%
7
100%
12
100%
Male
0
0%
0
0%
0
0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
0
0%
0
0%
0
0%
Not Hispanic or Latino
4
80%
5
71.4%
9
75%
Unknown or Not Reported
1
20%
2
28.6%
3
25%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
0
0%
0
0%
0
0%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
0
0%
0
0%
0
0%
White
4
80%
5
71.4%
9
75%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
1
20%
2
28.6%
3
25%
Region of Enrollment (participants) [Number]
United States
5
100%
7
100%
12
100%

Outcome Measures

1. Primary Outcome
Title Number of Participants With a Dose Limiting Toxicity (DLT) (Phase I)
Description Assessment of DLT for the patients in the atezolizumab and idasanutiln arm of the study
Time Frame At 28 days

Outcome Measure Data

Analysis Population Description
patients in the atezolizumab and idasanutiln arm of the study
Arm/Group Title Phase 1b - (Atezolizumab, Idasanutlin)
Arm/Group Description Atezolizumab: Given by IV Idasanutlin: Given by mouth
Measure Participants 7
Count of Participants [Participants]
1
20%
2. Primary Outcome
Title Maximum Tolerated Dose (Phase I)
Description Assessment of MTD for the atezolizumab and idasanutiln combination arm of the study
Time Frame At 28 days

Outcome Measure Data

Analysis Population Description
Patients in the atezolizumab and idasanutiln combination arm of the study. Dosage used: Atezolizumab 840mg IV + Idasanutlin 100mg PO
Arm/Group Title Phase 1b - (Atezolizumab, Idasanutlin)
Arm/Group Description Atezolizumab: Given by IV Idasanutlin: Given by mouth
Measure Participants 7
Number [mg]
NA
3. Primary Outcome
Title Recommended Phase II Dose (Phase I)
Description Assessment of recommended phase II dose for the atezolizumab and idasanutiln combination arm of the study
Time Frame At 28 days

Outcome Measure Data

Analysis Population Description
Patients on the atezolizumab and idasanutiln combination arm of the study. Dosage used: Atezolizumab 840mg IV + Idasanutlin 100mg PO.
Arm/Group Title Phase 1b - (Atezolizumab, Idasanutlin)
Arm/Group Description Atezolizumab: Given by IV Idasanutlin: Given by mouth
Measure Participants 7
Number [mg]
NA
4. Primary Outcome
Title Overall Response Rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST]1.1) (Phase II)
Description Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measure the rate (%) of complete and partial responses seen in patients with measurable disease. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame Up to 28 days after completion of study treatment, for a total of 2 years

Outcome Measure Data

Analysis Population Description
Patients on Phase 2 Arm 1 (TP53-mut) - Atezolizumab 840mg IV + Cobimetinib 60mg PO
Arm/Group Title Phase 2 (Atezolizumab, Cobimetinib)
Arm/Group Description Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by IV Cobimetinib: Given by mouth
Measure Participants 5
Number (95% Confidence Interval) [percentage of participants]
NA
NaN
5. Secondary Outcome
Title Clinical Benefit Rate (CBR) (Phase II)
Description Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measure the rate (%) of complete and partial responses + stability of disease at 6 months seen in patients with measurable disease. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame At 6 months

Outcome Measure Data

Analysis Population Description
patients on Phase 2 Arm 1 (TP53-mut) - Atezolizumab 840mg IV + Cobimetinib 60mg PO
Arm/Group Title Phase 2 (Atezolizumab, Cobimetinib)
Arm/Group Description Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by IV Cobimetinib: Given by mouth
Measure Participants 5
Number (95% Confidence Interval) [percentage of participants]
NA
NaN
6. Secondary Outcome
Title Immune Related Response Criteria (irRC) (Phase II)
Description Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measure the rate (%) of immune-related complete and partial responses seen in patients with measurable disease
Time Frame Up to 28 days after completion of study treatment, for a total of 2 years

Outcome Measure Data

Analysis Population Description
An insufficient number of participants exhibited response for analysis.
Arm/Group Title Phase 2 (Atezolizumab, Cobimetinib)
Arm/Group Description Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by IV Cobimetinib: Given by mouth
Measure Participants 0
7. Secondary Outcome
Title Progression-free Survival (PFS) (Phase II) in Days
Description Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measuring the interval (in months) between treatment initiation and disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1).
Time Frame At 12 months

Outcome Measure Data

Analysis Population Description
Patients on Phase 2 Arm 1 (TP53-mut) - Atezolizumab 840mg IV + Cobimetinib 60mg PO
Arm/Group Title Phase 2 (Atezolizumab, Cobimetinib)
Arm/Group Description Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by IV Cobimetinib: Given by mouth
Measure Participants 5
Median (95% Confidence Interval) [days]
56
8. Secondary Outcome
Title Overall Survival (OS) (Phase II) in Days
Description Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER + breast cancer by measuring the interval (in months) between treatment initiation and death from any cause
Time Frame At 12 months

Outcome Measure Data

Analysis Population Description
Patients on Phase 2 Arm 1 (TP53-mut) - Atezolizumab 840mg IV + Cobimetinib 60mg PO
Arm/Group Title Phase 2 (Atezolizumab, Cobimetinib)
Arm/Group Description Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by IV Cobimetinib: Given by mouth
Measure Participants 5
Median (95% Confidence Interval) [days]
161
9. Secondary Outcome
Title Number of Adverse Events (Phase II)
Description Assessment of adverse events throughout the phase II study
Time Frame Up to 28 days after completion of study treatment, for a total of 2 years

Outcome Measure Data

Analysis Population Description
patients on atezolizumab and cobimetinib.
Arm/Group Title Phase 2 (Atezolizumab, Cobimetinib)
Arm/Group Description Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by IV Cobimetinib: Given by mouth
Measure Participants 5
Number [events]
99

Adverse Events

Time Frame Initiation of study medication, throughout the study, and within 28 days (+/- 7 days) of the last dose of study medication, for a total of 2 years.
Adverse Event Reporting Description
Arm/Group Title Phase 2 (Atezolizumab, Cobimetinib) Phase 1b - (Atezolizumab, Idasanutlin)
Arm/Group Description Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by IV Cobimetinib: Given by mouth Atezolizumab: Given by IV Idasanutlin: Given by mouth
All Cause Mortality
Phase 2 (Atezolizumab, Cobimetinib) Phase 1b - (Atezolizumab, Idasanutlin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 3/5 (60%) 3/7 (42.9%)
Serious Adverse Events
Phase 2 (Atezolizumab, Cobimetinib) Phase 1b - (Atezolizumab, Idasanutlin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/5 (40%) 4/7 (57.1%)
Blood and lymphatic system disorders
Febrile neutropenia 0/5 (0%) 0 2/7 (28.6%) 2
Anemia 0/5 (0%) 0 1/7 (14.3%) 1
Gastrointestinal disorders
Vomiting 0/5 (0%) 0 1/7 (14.3%) 1
Infections and infestations
Strep infection 0/5 (0%) 0 1/7 (14.3%) 1
Lung infection 0/5 (0%) 0 1/7 (14.3%) 1
Investigations
Neutrophil count decreased 1/5 (20%) 1 2/7 (28.6%) 2
Platelet count decrease 0/5 (0%) 0 2/7 (28.6%) 2
White blood cell decreased 0/5 (0%) 0 1/7 (14.3%) 1
Death 0/5 (0%) 0 1/7 (14.3%) 1
Musculoskeletal and connective tissue disorders
Arthralgia 1/5 (20%) 1 0/7 (0%) 0
Back pain 1/5 (20%) 1 0/7 (0%) 0
Osteonecrosis 0/5 (0%) 0 1/7 (14.3%) 1
Psychiatric disorders
Suicide 0/5 (0%) 0 1/7 (14.3%) 1
Other (Not Including Serious) Adverse Events
Phase 2 (Atezolizumab, Cobimetinib) Phase 1b - (Atezolizumab, Idasanutlin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 5/5 (100%) 7/7 (100%)
Blood and lymphatic system disorders
Anemia 4/5 (80%) 8 4/7 (57.1%) 5
Leukocytosis 0/5 (0%) 0 1/7 (14.3%) 1
Lymph node pain 1/5 (20%) 1 0/7 (0%) 0
Ear and labyrinth disorders
Ear pain 0/5 (0%) 0 1/7 (14.3%) 1
Endocrine disorders
Hypothyroidism 0/5 (0%) 0 1/7 (14.3%) 1
Eye disorders
Blurred vison 0/5 (0%) 0 2/7 (28.6%) 2
Glaucoma 1/5 (20%) 1 0/7 (0%) 0
Retinopathy 1/5 (20%) 1 0/7 (0%) 0
Gastrointestinal disorders
Diarrhea 3/5 (60%) 5 5/7 (71.4%) 9
Nausea 3/5 (60%) 5 5/7 (71.4%) 12
Vomiting 3/5 (60%) 7 4/7 (57.1%) 7
Constipation 2/5 (40%) 4 3/7 (42.9%) 4
Abdominal pain 1/5 (20%) 1 2/7 (28.6%) 3
Dyspepsia 0/5 (0%) 0 3/7 (42.9%) 9
Dry mouth 1/5 (20%) 1 1/7 (14.3%) 1
Dysphagia 1/5 (20%) 1 1/7 (14.3%) 1
Flatulence 1/5 (20%) 1 1/7 (14.3%) 1
Bloating 0/5 (0%) 0 1/7 (14.3%) 1
Esophagitis 0/5 (0%) 0 1/7 (14.3%) 1
Gingival pain 0/5 (0%) 0 1/7 (14.3%) 1
Mucositis oral 0/5 (0%) 0 1/7 (14.3%) 1
Tooth ache 1/5 (20%) 1 0/7 (0%) 0
General disorders
Fatigue 3/5 (60%) 6 5/7 (71.4%) 9
Fever 1/5 (20%) 2 1/7 (14.3%) 1
Malaise 1/5 (20%) 1 1/7 (14.3%) 1
Non-cardiac chest pain 0/5 (0%) 0 1/7 (14.3%) 3
Pain 1/5 (20%) 1 0/7 (0%) 0
Hepatobiliary disorders
Postnasal drip 0/5 (0%) 0 1/7 (14.3%) 1
Hepatic pain 2/5 (40%) 3 0/7 (0%) 0
Infections and infestations
Sinusitis 1/5 (20%) 1 1/7 (14.3%) 1
Upper respiratory infection 2/5 (40%) 2 0/7 (0%) 0
Urinary tract infection 1/5 (20%) 1 1/7 (14.3%) 1
Bronchial infection 0/5 (0%) 0 1/7 (14.3%) 1
Skin infection 0/5 (0%) 0 1/7 (14.3%) 1
Injury, poisoning and procedural complications
Blood bilirubin increased 0/5 (0%) 0 1/7 (14.3%) 1
Fall 1/5 (20%) 1 1/7 (14.3%) 1
Bruising 0/5 (0%) 0 1/7 (14.3%) 1
Investigations
Lymphocyte count decreased 4/5 (80%) 9 4/7 (57.1%) 12
White blood cell decreased 3/5 (60%) 8 5/7 (71.4%) 13
Neutrophil count decreased 2/5 (40%) 3 2/7 (28.6%) 5
Aspartate aminotransferase increased 3/5 (60%) 6 3/7 (42.9%) 3
Platelet count decreased 1/5 (20%) 2 2/7 (28.6%) 12
Alanine aminotransferase increased 3/5 (60%) 6 1/7 (14.3%) 1
Alkaline phosphatase increased 1/5 (20%) 2 2/7 (28.6%) 3
Cholesterol high 0/5 (0%) 0 1/7 (14.3%) 1
GGT increased 1/5 (20%) 1 0/7 (0%) 0
INR increased 0/5 (0%) 0 1/7 (14.3%) 1
Lymphocyte count increased 0/5 (0%) 0 1/7 (14.3%) 1
Hypokalemia 3/5 (60%) 5 1/7 (14.3%) 1
Metabolism and nutrition disorders
Anorexia 3/5 (60%) 4 4/7 (57.1%) 7
Hyperglycemia 2/5 (40%) 5 4/7 (57.1%) 10
Hypoalbuminemia 2/5 (40%) 6 2/7 (28.6%) 2
Dehydration 1/5 (20%) 1 2/7 (28.6%) 3
Hypocalcemia 1/5 (20%) 1 2/7 (28.6%) 3
Hyponatremia 1/5 (20%) 1 1/7 (14.3%) 1
Hypercalcemia 1/5 (20%) 4 0/7 (0%) 0
Hyperuricemia 1/5 (20%) 1 0/7 (0%) 0
Hypomagnesemia 1/5 (20%) 1 0/7 (0%) 0
Hypophosphatemia 1/5 (20%) 2 0/7 (0%) 0
Musculoskeletal and connective tissue disorders
Arthralgia 2/5 (40%) 6 2/7 (28.6%) 3
Back pain 1/5 (20%) 3 2/7 (28.6%) 2
Flank pain 0/5 (0%) 0 1/7 (14.3%) 2
Myalgia 0/5 (0%) 0 1/7 (14.3%) 1
Neck pain 1/5 (20%) 1 0/7 (0%) 0
Pain in extremity 0/5 (0%) 0 1/7 (14.3%) 1
Nervous system disorders
Headache 1/5 (20%) 1 3/7 (42.9%) 5
Dysgeusia 2/5 (40%) 3 1/7 (14.3%) 1
Peripheral sensory neuropathy 0/5 (0%) 0 2/7 (28.6%) 2
Dizziness 0/5 (0%) 0 1/7 (14.3%) 1
Neuralgia 0/5 (0%) 0 1/7 (14.3%) 1
Psychiatric disorders
Insomnia 0/5 (0%) 0 2/7 (28.6%) 2
Depression 0/5 (0%) 0 1/7 (14.3%) 2
Renal and urinary disorders
Hematuria 0/5 (0%) 0 1/7 (14.3%) 1
Urinary tract obstruction 0/5 (0%) 0 1/7 (14.3%) 3
Reproductive system and breast disorders
Pelvic pain 0/5 (0%) 0 1/7 (14.3%) 1
Vaginal dryness 0/5 (0%) 0 1/7 (14.3%) 1
Respiratory, thoracic and mediastinal disorders
Cough 1/5 (20%) 2/7 (28.6%) 2
Dyspnea 1/5 (20%) 1 2/7 (28.6%) 3
Productive cough 1/5 (20%) 1 1/7 (14.3%) 1
Sore throat 0/5 (0%) 0 2/7 (28.6%) 3
Epistaxis 1/5 (20%) 1 0/7 (0%) 0
Pleural effusion 1/5 (20%) 1 0/7 (0%) 0
Pulmonary edema 1/5 (20%) 1 0/7 (0%) 0
Skin and subcutaneous tissue disorders
Pruritus 1/5 (20%) 2 1/7 (14.3%) 1
Rash maculo-papular 0/5 (0%) 0 2/7 (28.6%) 4
Alopecia 0/5 (0%) 0 1/7 (14.3%) 1
Dry skin 1/5 (20%) 2 0/7 (0%) 0
Hyperhidrosis 0/5 (0%) 0 1/7 (14.3%) 1
Rash acneiform 1/5 (20%) 1 0/7 (0%) 0
Scalp pain 1/5 (20%) 1 0/7 (0%) 0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Teresa Melton
Organization Vanderbilt-Ingram Cancer Center
Phone 6159367423
Email teresa.melton@vumc.org
Responsible Party:
Ingrid Mayer, MD, Principal Investigator, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier:
NCT03566485
Other Study ID Numbers:
  • VICC BRE 17107
  • NCI-2018-01159
First Posted:
Jun 25, 2018
Last Update Posted:
Aug 11, 2021
Last Verified:
Aug 1, 2021