Brain Irradiation and Tremelimumab in Metastatic Breast Cancer

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02563925
• Collaborator: MedImmune LLC (Industry)
• Enrollment: 28
• Location: 1
• Arm: 1
• Actual Duration (Months): 69.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to see if the combination of tremelimumab and durvalumab with brain radiation therapy can help treat this type of breast cancer that has spread to the brain.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Radiation: Brain radiotherapy or Stereotactic Radiosurgery; Drug: Tremelimumab; Drug: HER2 directed therapy; Drug: Durvalumab	N/A

Detailed Description

A Simon 2-stage single-arm design (n=17) will be employed to evaluate for preliminary efficacy. A maximum of 17 subjects will be accrued to the efficacy arm. After the first 3 patients are enrolled in the efficacy arm, a 6 week enrollment hold will be conducted in order to ensure safety before additional patients are enrolled. An interim assessment will then occur after the first 9 subjects have enrolled, and the accrual to this arm will proceed only if a pre-specified futility threshold is met. Patients not requiring continuation of HER2 directed therapy, such as trastuzumab, will be enrolled in this arm.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Brain Irradiation and Tremelimumab in Metastatic Breast Cancer
• Actual Study Start Date: Sep 18, 2015
• Actual Primary Completion Date: Jul 14, 2021
• Actual Study Completion Date: Jul 14, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Radiation and Tremelimumab Subjects will get either whole brain radiation treatment (WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with tremelimumab administered every 28 days. Patients, for whom concurrent HER2 directed therapy trastuzumab is indicated, as determined by the treating investigator, will be enrolled in a parallel HER2 directed therapy trastuzumab safety cohort. Protocol Expansion: Dose 1 of tremelimumab & durvalumab (75 mg & 1500 mg, respectively) will ideally be administered 2 days prior to initiation of brain radiotherapy (or between 5 days prior & 3 days after initiation of radiotherapy). Subjects will get either WBRT or SRS, depending on the number & size of their brain metastases. Following the 1st dose, tremelimumab & duvralumab will be administered q28 days from the date of 1st tremelimumab & durvalumab administration, plus or minus 1 week, for 4 cycles. After the 4th cycle, durvalumab will be administered alone until progression of disease or unacceptable toxicity.

Radiation: Brain radiotherapy or Stereotactic Radiosurgery; Drug: Tremelimumab; Drug: HER2 directed therapy; Drug: Durvalumab

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (irPFS) [12 week]

   will be defined as the time from the first dose of tremelimumab until death or progressive disease, as measured by irRC. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Secondary Outcome Measures

1. Participants Assessed for Toxicity Using the NCI CTCAE 4.0 [1 year]

   safety profile assessed with regular physical examination and toxicity assessment using the NCI CTCAE 4.0. Subjects will be followed with regular radiation oncology assessments as per the standard of care.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of CNS metastases for whom SRS or WBRT is indicated, as determined by radiation oncologist assessment

• Age 18 and older at the time of consent

• Written informed consent and authorization obtained from the subject/HIPAA-appointed legal representative prior to performing any protocol-related procedures including screening evaluations

• ECOG performance of 0-2 with anticipated life expectancy of ≥12 weeks

• Histologically or cytologically confirmed invasive breast cancer that is HER2-positive (3+ by IHC and/or >2.0 by FISH) if concurrent HER2-directed therapy is planned;

• Non-CNS progression of disease as assessed by the investigator/treating physician, for which a change in systemic therapy is planned OR achievement of stable or responsive non-CNS disease for which a holiday from the current systemic therapy is planned, as assessed by the investigator/treating physician.

• Measurable non-CNS disease, defined by RECIST1.1 criteria

• Recovered from all toxicities associated with prior treatment, to acceptable baseline status or grade 1 or less (for lab toxicities see below limits for inclusion,), except for toxicities not considered a safety risk, such as alopecia or vitiligo. Peripheral neuropathy must be grade 2 or less

• Adequate organ and marrow function, as defined below:

• platelets ≥ 75x 103/μL;

• absolute neutrophil count (ANC) ≥ 1,000/μL;

• hemoglobin ≥ 9.0 g/dL;

• total bilirubin ≤1.5 x ULN (upper limit of normal) except subject with documented Gilbert's syndrome (≤5 x ULN) or liver metastasis, who must have a baseline total bilirubin ≤3.0 mg/dL;

• AST and ALT ≤ 3 x ULN, unless associated with hepatobiliary metastases, in that case ≤5 x ULN

• serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 50 ml/min as determined by the Cockcroft-Gault equation);

• Negative hepatitis B serologic tests. If positive results are not indicative of active or chronic infection, the subjects can enter the study at the investigator's discretion

• Females of childbearing potential who are sexually active with a non-sterilized male partner must use a highly effective method of contraception prior to the first dose of investigational product, and must agree to continue using such precautions for 6 months after the final dose of investigational product; cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. They must also refrain from egg cell donation for 6 months after the final dose of investigational product;

• Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause);

• A highly effective method of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. The acceptable methods of contraception

• Non-sterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from Days 1 through 90 post last dose. In addition, they must refrain from sperm donation for 90 days after the final dose of investigational product

• LVEF ≥50% for patients enrolling in the HER2 directed therapy arm

• Willing to attempt a baseline tumor biopsy procedure

Exclusion Criteria:

• CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt placement)

• Known leptomeningeal metastases not amenable to radiotherapy. Patients receiving radiotherapy for leptomeningeal metastases are eligible

• Received any prior monoclonal antibody against CTLA-4, programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PD-L1)

• Subjects with a history of hypersensitivity to compounds of similar biologic composition to tremelimumab or any constituent of the product

• Subjects with a history of hypersensitivity to compounds of similar biologic composition to durvalumab or any constituent of the product;

• Patients unable to obtain MRI for any reason (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme obesity)

• Concurrent enrollment in another therapeutic clinical study or receipt of an investigational product within the last 4 weeks (participation in the survival follow-up period of a study is not an exclusion criterion)

• Medical conditions (aside from newly-diagnosed brain metastases) for which the chronic use of corticosteroids or other immunosuppressive medications are indicated. Note: inhaled and topical steroids are permitted

• Use of immunosuppressive medications within 14 days before the first dose of study drug. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection); systemic corticosteroids at physiological doses not to exceed 10mg/day of prednisone or its equivalent; steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication).

• Subjects should not be vaccinated with live attenuated vaccines within one month prior to starting tremelimumab treatment

• Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results

• Any serious uncontrolled medical disorder or active infection that would impair the subject's ability to receive investigational product, such as conditions associated with frequent diarrhea

• Active or history of autoimmune or inflammatory disorders, including inflammatory bowel disease (e.g., colitis, Crohn's), diverticulitis (with the exception of diverticulosis), irritable bowel disease, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener's granulomatosis, Sarcoidosis syndrome, Addison's disease, multiple sclerosis, Graves' disease, Hashimoto's thyroiditis, rheumatoid arthritis, hypophysitis, uveitis, etc. Patients without active disease in the last 5 years may be included but only after consultation with the study physician. Note: the following are exceptions to this criterion: Vitiligo or alopecia; patients with hypothyroidism (i.e. following Hashimoto syndrome) stable on hormone replacement; any chronic skin condition that does not require systemic therapy; patients with celiac disease controlled by diet alone;

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

• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, active peptic ulcer disease or gastritis, and active bleeding diatheses;

• Known history of previous clinical diagnosis of tuberculosis;

• History of allogeneic organ transplant;

• History of leptomeningeal carcinomatosis

• No active, second potentially life-threatening cancer. No history of another primary malignancy except for; malignancy treated with curative intent and no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma in situ without evidence of disease;

• Pregnant or breast feeding at time of consent

• Any condition that would prohibit the understanding or rendering of information and consent and compliance with the requirements of this protocol

• Known positive for HIV, chronic or active hepatitis B or C

• Patient is unable to receive IV contrast

• Neuroimaging evidence of midline shift

• Major surgical procedure, as defined by the investigator, within 28 days prior to the first dose of IP. Note: Local surgery or isolated lesions for palliative intent is acceptable.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• MedImmune LLC

Investigators

• Principal Investigator: Shanu Modi, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 29, 2018

More Information

Additional Information:

• Memorial Sloan Kettering Cancer Center

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT02563925
• Other Study ID Numbers: 15-038
• First Posted: Sep 30, 2015
• Last Update Posted: Aug 3, 2022
• Last Verified: Jul 1, 2020

• Keywords provided by Memorial Sloan Kettering Cancer Center: Brain Irradiation; Tremelimumab; 15-038
• Additional relevant MeSH terms: Breast Neoplasms; Durvalumab; Tremelimumab

Study Results

Participant Flow

Arm/Group Title	Radiation and Tremelimumab
Arm/Group Description	Subjects will get either whole brain radiation treatment (WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with tremelimumab administered every 28 days. Patients, for whom concurrent HER2 directed therapy trastuzumab is indicated, as determined by the treating investigator, will be enrolled in a parallel HER2 directed therapy trastuzumab safety cohort.
Period Title: Overall Study
STARTED	28
COMPLETED	26
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Radiation and Tremelimumab
Arm/Group Description	Subjects will get either whole brain radiation treatment (WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with tremelimumab administered every 28 days. Patients, for whom concurrent HER2 directed therapy trastuzumab is indicated, as determined by the treating investigator, will be enrolled in a parallel HER2 directed therapy trastuzumab safety cohort.
Overall Participants	28
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	50
Sex: Female, Male (Count of Participants)
Female	28 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	28 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	5 17.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 17.9%
White	17 60.7%
More than one race	0 0%
Unknown or Not Reported	1 3.6%
Region of Enrollment (Count of Participants)
United States	28 100%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (irPFS)
Description	will be defined as the time from the first dose of tremelimumab until death or progressive disease, as measured by irRC. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	12 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Radiation and Tremelimumab
Arm/Group Description	Subjects will get either whole brain radiation treatment (WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with tremelimumab administered every 28 days. Patients, for whom concurrent HER2 directed therapy trastuzumab is indicated, as determined by the treating investigator, will be enrolled in a parallel HER2 directed therapy trastuzumab safety cohort.
Measure Participants	28
Progressive Disease	21 75%
Death	1 3.6%
Stable Disease	3 10.7%
Partial Response	1 3.6%
Not Evaluable	2 7.1%

2. Secondary Outcome

Title	Participants Assessed for Toxicity Using the NCI CTCAE 4.0
Description	safety profile assessed with regular physical examination and toxicity assessment using the NCI CTCAE 4.0. Subjects will be followed with regular radiation oncology assessments as per the standard of care.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Radiation and Tremelimumab
Arm/Group Description	Subjects will get either whole brain radiation treatment (WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with tremelimumab administered every 28 days. Patients, for whom concurrent HER2 directed therapy trastuzumab is indicated, as determined by the treating investigator, will be enrolled in a parallel HER2 directed therapy trastuzumab safety cohort. Protocol Expansion: Dose 1 of tremelimumab & durvalumab (75 mg & 1500 mg, respectively) will ideally be administered 2 days prior to initiation of brain radiotherapy (or between 5 days prior & 3 days after initiation of radiotherapy). Subjects will get either WBRT or SRS, depending on the number & size of their brain metastases. Following the 1st dose, tremelimumab & duvralumab will be administered q28 days from the date of 1st tremelimumab & durvalumab administration, plus or minus 1 week, for 4 cycles. After the 4th cycle, durvalumab will be administered alone until progression of disease or unacceptable toxicity. Brain radiotherapy or Stereotactic Radiosurgery Tremelimumab HER2 directed therapy Durvalumab
Measure Participants	28
Count of Participants [Participants]	28 100%

Adverse Events

Time Frame	1 year
Arm/Group Title	Radiation and Tremelimumab
Arm/Group Description	Subjects will get either whole brain radiation treatment (WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with tremelimumab administered every 28 days. Patients, for whom concurrent HER2 directed therapy trastuzumab is indicated, as determined by the treating investigator, will be enrolled in a parallel HER2 directed therapy trastuzumab safety cohort.
All Cause Mortality
	Radiation and Tremelimumab
	Affected / at Risk (%)	# Events
Total	27/28 (96.4%)
Serious Adverse Events
	Radiation and Tremelimumab
	Affected / at Risk (%)	# Events
Total	20/28 (71.4%)
Cardiac disorders
Sinus tachycardia	1/28 (3.6%)
Gastrointestinal disorders
Abdominal Distension	1/28 (3.6%)
Abdominal Pain	3/28 (10.7%)
Ascites	2/28 (7.1%)
Colitis	3/28 (10.7%)
Diarrhea	4/28 (14.3%)
Dysphagia	2/28 (7.1%)
Esophagitis	1/28 (3.6%)
Nausea	3/28 (10.7%)
Vomiting	2/28 (7.1%)
General disorders
Death NOS	1/28 (3.6%)
Neck edema	1/28 (3.6%)
Pain	1/28 (3.6%)
Infections and infestations
Urinary tract infection	1/28 (3.6%)
Investigations
Alanine aminotransferase increased	1/28 (3.6%)
Aspartate aminotransferase increased	2/28 (7.1%)
Blood bilirubin increased	1/28 (3.6%)
Neutrophil count decreased	1/28 (3.6%)
Platelet count decreased	1/28 (3.6%)
Metabolism and nutrition disorders
Dehydration	1/28 (3.6%)
Hypercalcemia	2/28 (7.1%)
Hyponatremia	1/28 (3.6%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	3/28 (10.7%)
Pain in extremity	2/28 (7.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms ben/mal/unk (inc cyst/polyp) Other, spec	8/28 (28.6%)
Nervous system disorders
Ataxia	1/28 (3.6%)
Cognitive disturbance	1/28 (3.6%)
Dysphasia	1/28 (3.6%)
Facial nerve disorder	1/28 (3.6%)
Headache	1/28 (3.6%)
Somnolence	1/28 (3.6%)
Psychiatric disorders
Confusion	2/28 (7.1%)
Reproductive system and breast disorders
Breast pain	1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Cough	1/28 (3.6%)
Dyspnea	4/28 (14.3%)
Hypoxia	3/28 (10.7%)
Pleural effusion	1/28 (3.6%)
Vascular disorders
Hypertension	1/28 (3.6%)
Hypotension	1/28 (3.6%)
Other (Not Including Serious) Adverse Events
	Radiation and Tremelimumab
	Affected / at Risk (%)	# Events
Total	26/28 (92.9%)
Blood and lymphatic system disorders
Anemia	2/28 (7.1%)
Endocrine disorders
Hypothyroidism	2/28 (7.1%)
Gastrointestinal disorders
Nausea	11/28 (39.3%)
Vomiting	9/28 (32.1%)
Colitis	6/28 (21.4%)
Diarrhea	6/28 (21.4%)
Constipation	5/28 (17.9%)
Dry Mouth	4/28 (14.3%)
Mucositis oral	4/28 (14.3%)
Abdominal pain	3/28 (10.7%)
Dysphagia	2/28 (7.1%)
Gastroesophageal reflux disease	2/28 (7.1%)
General disorders
Fatigue	10/28 (35.7%)
Pain	3/28 (10.7%)
Gen disorders & admin site conditions Other, spec	2/28 (7.1%)
Malaise	2/28 (7.1%)
Investigations
Weight loss	10/28 (35.7%)
Alkaline phosphatase increased	3/28 (10.7%)
Alanine aminotransferase increased	2/28 (7.1%)
Aspartate aminotransferase increased	2/28 (7.1%)
Investigations - Other, specify	2/28 (7.1%)
Metabolism and nutrition disorders
Anorexia	14/28 (50%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	4/28 (14.3%)
Back pain	2/28 (7.1%)
Nervous system disorders
Headache	5/28 (17.9%)
Dizziness	4/28 (14.3%)
Dysgeusia	4/28 (14.3%)
Ataxia	3/28 (10.7%)
Respiratory, thoracic and mediastinal disorders
Cough	9/28 (32.1%)
Dyspnea	4/28 (14.3%)
Resp, thoracic & mediastinal disorder Other, spec	2/28 (7.1%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	5/28 (17.9%)
Pruritus	3/28 (10.7%)
Urticaria	3/28 (10.7%)
Alopecia	2/28 (7.1%)
Dry skin	2/28 (7.1%)
Skin hyperpigmentation	2/28 (7.1%)

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.