A phase I/II study to evaluate the safety, tolerability, and preliminary efficacy of KW-2450 in combination with lapatinib and letrozole in subjects with advanced or metastatic breast cancer whose tumor overexpress HER2
The goal of Phase 1 of this clinical research study is to find the highest tolerable dose of KW-2450 when given in combination with lapatinib and letrozole to patients with advanced breast cancer. The safety of this drug combination will also be studied.
Disease Group: Breast
Treatment Agent: KW-2450
Treatment Location: Both at MD Anderson & Other Sites
Sponsor: Kyowa Hakko Kirin Pharma, Inc
Primary Objectives Phase 1 To establish the safety, tolerability, and recommended Phase 2 dose of KW-2450 administered in combination with lapatinib and letrozole in subjects with previously treated or untreated HER2+ advanced breast cancer. Phase 2 To establish the safety and preliminary efficacy based on the Clinical Benefit Rate (CBR) for the combination of lapatinib and letrozole with KW-2450 at the recommended dose in subjects with previously untreated HER2+ advanced breast cancers. Secondary Objectives 1. To determine the pharmacokinetic profile of KW-2450, lapatinib, and letrozole when administered in combination 2. To evaluate the exploratory pharmacodynamic biomarkers of IGF-1R inhibition by KW-2450 in serum, tumor tissue (if applicable), for their potential as markers of therapeutic efficacy.
IRB Review and Approval Date: 06/13/2011
Recruitment Status: Not Accepting
Projected Accrual: 198
1) Sign Institutional Review Board (IRB) approved informed consent form
in accordance with regulatory and institutional guidelines;
2) Histopathologically or cytologically confirmed, advanced or metastatic breast cancer (stage IIIb, IIIc or IV disease) including inflammatory breast cancer or inoperable locally advanced disease. For the Phase 2 portion no prior therapy for metastatic disease will be allowed. Patients may have received prior neoadjuvant or adjuvant therapy including chemotherapy, aromatase inhibitors, antiestrogens, and trastuzumab provided that all such therapy had been discontinued one year prior to study entry. Patients may have received prior aromatase inhibitors as a single agent for up to 3 months prior to study enrollment;
3) Documented ErbB2 overexpression as IHC staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1+, a FISH result of less than 4.0 HER2 gene copies per nucleus, or FISH ratio of less than 1.8 based on local laboratory or initial diagnostic results;
4) Estrogen receptor positive (ER+) and/or progesterone positive (PgR+) tumors;
5) Measurable or non-measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria;
6) Ability to comply with visits/procedures required by the protocol. Subjects enrolled in this trial must be treated at a participating center;
7) A life expectancy of > 3 months in Phase 1 and > 6 months in Phase 2;
8) Eastern Cooperative Oncology Group (ECOG) performance status score of </= 2 at study entry in Phase 1 and </= 1 in Phase 2.
9) Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram (or MUGA scan if an echocardiogram cannot be performed or is inconclusive) evaluated within 21 days of study enrollment;
10) Adequate hematologic function, as defined by: an absolute neutrophil count (ANC) >/= 1500/mm^3; a hemoglobin level >/= 8.5 gm/dL; a platelet count >/= 100,000/mm^3;
11) Adequate hepatic function, as defined by: a total bilirubin level </= 1.5 x the upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine transaminase (ALT) levels </= 2.5 x the ULN or </= 5 x the ULN if known liver metastases;
12) Adequate renal function, as defined by: a serum creatinine (Scr) </= 1.5 mg/dL for male subjects; Scr </=1.40 mg/dL for female subjects; or Calculated creatinine clearance > 60 mL/min based on Cockcroft-Gault formula
13) Subjects must be recovered from the effects of any prior anti-neoplastic therapy. The ongoing adverse events (AEs) due to these therapies must be </= Grade 1 prior to entering the study. At least 5 half-lives should have elapsed for any investigational agents prior to the administration of study medication
14) Female subjects must be post-menopausal, defined by any of the following: Age > 60 years or; Age >/= 46 years with amenorrhea > 12 months with an intact uterus; Having undergone a bilateral oophorectomy or radiation castration with amenorrhea for at least 6 months or: Age </= 45 follicle-stimulating hormone (FSH) and estradiol levels in postmenopausal range (utilizing ranges from the local laboratory facility)
15) Post-menopausal female or male subjects >/= 18 years of age at the time of enrollment;
16) Male subjects must be willing to use an appropriate method of contraception (e.g., condoms) or abstain from sexual intercourse and inform any sexual partners that they must also use a reliable method of contraception (e.g., birth control pills) during the study and for 90 days following the last dose of study medication.
1) Type 1 diabetes or uncontrolled Type 2 diabetes as defined as:
Fasting plasma glucose (FPG) >/=160 mg/dL; or HbA1c >/= 8 % or:
albuminuria < 300 mg/g; or foot ulcer > 3 mm diameter or chronic
osteomyelitis of lower extremity, or claudication that prevents walking
or; requiring the routine use of insulin;
2) Subjects showing clinical evidence or with a history of cataract(s), proliferate retinopathy or significant macular edema, history of vitreous hemorrhage, photocoagulation or vitrectomy;
3) Abnormal free T4 values. Abnormal thyroid stimulating hormone (TSH) values at enrollment will be further evaluated by free T4. Subjects with abnormal free T4 values and a history or evidence of thyroid disease will be excluded.
4) Subjects who are unable or unwilling to take metformin;
5) Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection requiring parenteral antibiotics; A serious or nonhealing active wound, ulcer, or bone fracture; Uncontrolled hypertension (systolic blood pressure > 160 mmHg, diastolic blood pressure > 100 mmHg, found on two consecutive measurements separated by a 1week period despite treatment with two antihypertensive agents);
6) Unstable cardiovascular disease (i.e., uncontrolled ischemic heart disease, congestive heart failure, arrhythmia or hypertension; New York Heart Association [NYHA, Appendix 2] >/= class III; or myocardial infarction or acute coronary syndrome within 6 months);
7) Known or suspected human immunodeficiency virus (HIV) infection or hepatitis B or C;
8) Subjects with inflammatory diseases of the gastrointestinal tract or malabsorption syndrome, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded
9) Major surgery within 4 weeks prior to the administration of study medication;
10) History of other malignancy. Subjects who have been disease free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible;
11) Subjects with extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor;
12) Evidence of organ dysfunction or any clinically significant deviation in physical examination, vital signs, or clinical laboratory determination;
13) QTcF of >450 msec or any clinically significant abnormalities on ECG;
14) Prior treatment with lapatinib (for the Phase 1 portion, it is permitted that subjects may have received prior lapatinib treatment up to 3 months prior to study enrollment) and letrozole (For the Phase 1 portion, it is permitted that subjects may have received prior aromatase inhibitors as a single agent for up to 4 weeks prior to study enrollment)
15) A history of prior treatment with other agents specifically targeting IGFRs;(i.e. ganitumab, AVE1642, BIIB022, BMS-754807, figitumumab, cixutumumab, dalotuzumab, linsitinib)
16) Subjects who require pharmacological doses of glucocorticoids beyond replacement doses. The use of topical, intra-ocular or inhalation glucocorticoids is permitted;
17) Strong inhibitors/inducers of CYP3A4/5, herbal medications (within 1 week of administration of study medication), or drugs for prevention of graft versus host disease or transplant rejection (within 2 months prior to the administration of study medication);
18) Hematopoietic growth factors and erythropoiesis-stimulating agents within 3 weeks prior to the administration of study medication.